Some medically important viruses-including retroviruses, flaviviruses, coronaviruses, and herpesviruses-code for a protease, which is indispensable for viral maturation and pathogenesis. Viral protease inhibitors have become an important class of antiviral drugs. Development of the first-in-class viral protease inhibitor saquinavir, which targets HIV protease, started a new era in the treatment of chronic viral diseases. Combining several drugs that target different steps of the viral life cycle enables use of lower doses of individual drugs (and thereby reduction of potential side effects, which frequently occur during long term therapy) and reduces drug-resistance development. Currently, several HIV and HCV protease inhibitors are routinely used in clinical practice. In addition, a drug including an inhibitor of SARS-CoV-2 main protease, nirmatrelvir (co-administered with a pharmacokinetic booster ritonavir as Paxlovid®), was recently authorized for emergency use. This review summarizes the basic features of the proteases of human immunodeficiency virus (HIV), hepatitis C virus (HCV), and SARS-CoV-2 and discusses the properties of their inhibitors in clinical use, as well as development of compounds in the pipeline.

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo nám 2 166 10 Prague 6 Czech Republic

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo nám 2 166 10 Prague 6 Czech Republic; Department of Biochemistry Faculty of Science Charles University Prague 128 43 Prague Czech Republic

Zobrazit více v PubMed

Achdout H., Aimon A., Bar-David E., Barr H., Ben-Shmuel A., Bennett J., Bilenko V.A., Bilenko V.A., Boby M.L., Borden B., Bowman G.R., Brun J., Bvnbs S., Calmiano M., Carbery A., Carney D., Cattermole E., Chang E., Chernyshenko E., Chodera J.D., Clyde A., Coffland J.E., Cohen G., Cole J., Contini A., Cox L., Cvitkovic M., Dias A., Donckers K., Dotson D.L., Douangamath A., Duberstein S., Dudgeon T., Dunnett L., Eastman P.K., Erez N., Eyermann C.J., Fairhead M., Fate G., Fearon D., Fedorov O., Ferla M., Fernandes R.S., Ferrins L., Foster R., Foster H., Gabizon R., Garcia-Sastre A., Gawriljuk V.O., Gehrtz P., Gileadi C., Giroud C., Glass W.G., Glen R., Glinert I., Godoy A.S., Gorichko M., Gorrie-Stone T., Griffen E.J., Hart S.H., Heer J., Henry M., Hill M., Horrell S., Huliak V.D., Hurley M.F.D., Israely T., Jajack A., Jansen J., Jnoff E., Jochmans D., John T., Jonghe S.D., Kantsadi A.L., Kenny P.W., Kiappes J.L., Kinakh S.O., Koekemoer L., Kovar B., Krojer T., Lee A., Lefker B.A., Levy H., Logvinenko I.G., London N., Lukacik P., Macdonald H.B., MacLean B., Malla T.R., Matviiuk T., McCorkindale W., McGovern B.L., Melamed S., Melnykov K.P., Michurin O., Mikolajek H., Milne B.F., Morris A., Morris G.M., Morwitzer M.J., Moustakas D., Nakamura A.M., Neto J.B., Neyts J., Nguyen L., Noske G.D., Oleinikovas V., Oliva G., Overheul G.J., Owen D., Pai R., Pan J., Paran N., Perry B., Pingle M., Pinjari J., Politi B., Powell A., Psenak V., Puni R., Rangel V.L., Reddi R.N., Reid S.P., Resnick E., Ripka E.G., Robinson M.C., Robinson R.P., Rodriguez-Guerra J., Rosales R., Rufa D., Saar K., Saikatendu K.S., Schofield C., Shafeev M., Shaikh A., Shi J., Shurrush K., Singh S., Sittner A., Skyner R., Smalley A., Smeets B., Smilova M.D., Solmesky L.J., Spencer J., Strain-Damerell C., Swamy V., Tamir H., Tennant R., Thompson W., Thompson A., Tomasio S., Tsurupa I.S., Tumber A., Vakonakis I., van Rij R.P., Vangeel L., Varghese F.S., Vaschetto M., Vitner E.B., Voelz V., Volkamer A., von Delft F., von Delft A., Walsh M., Ward W., Weatherall C., Weiss S., White K.M., Wild C.F., Wittmann M., Wright N., Yahalom-Ronen Y., Zaidmann D., Zidane H., Zitzmann N. bioRxiv; 2022. Open Science Discovery of Oral Non-covalent SARS-CoV-2 Main Protease Inhibitor Therapeutics. 2020.2010.2029.339317. DOI

Akaberi D., Båhlström A., Chinthakindi P.K., Nyman T., Sandström A., Järhult J.D., Palanisamy N., Lundkvist Å., Lennerstrand J. Targeting the NS2B-NS3 protease of tick-borne encephalitis virus with pan-flaviviral protease inhibitors. Antivir. Res. 2021;190 doi: 10.1016/j.antiviral.2021.105074. PubMed DOI

Alazard-Dany N., Denolly S., Boson B., Cosset F.-L. Overview of HCV life cycle with a special focus on current and possible future antiviral targets. Viruses. 2019;11(1):30. doi: 10.3390/v11010030. PubMed DOI PMC

Aleshin A.E., Drag M., Gombosuren N., Wei G., Mikolajczyk J., Satterthwait A.C., Strongin A.Y., Liddington R.C., Salvesen G.S. Activity, specificity, and probe design for the smallpox virus protease K7L. J. Biol. Chem. 2012;287(47):39470–39479. doi: 10.1074/jbc.M112.388678. PubMed DOI PMC

Allegra A., Innao V., Allegra A.G., Pulvirenti N., Pugliese M., Musolino C. Antitumorigenic action of nelfinavir: effects on multiple myeloma and hematologic malignancies (Review) Oncol. Rep. 2020;43(6):1729–1736. doi: 10.3892/or.2020.7562. PubMed DOI

Alvi R.M., Neilan A.M., Tariq N., Awadalla M., Afshar M., Banerji D., Rokicki A., Mulligan C., Triant V.A., Zanni M.V., Neilan T.G. Protease inhibitors and cardiovascular outcomes in patients with HIV and heart failure. J. Am. Coll. Cardiol. 2018;72(5):518–530. doi: 10.1016/j.jacc.2018.04.083. PubMed DOI PMC

Aoki M., Venzon D.J., Koh Y., Aoki-Ogata H., Miyakawa T., Yoshimura K., Maeda K., Mitsuya H. Non-cleavage site gag mutations in amprenavir-resistant human immunodeficiency virus type 1 (HIV-1) predispose HIV-1 to rapid acquisition of amprenavir resistance but delay development of resistance to other protease inhibitors. J. Virol. 2009;83(7):3059–3068. doi: 10.1128/jvi.02539-08. PubMed DOI PMC

Aoki M., Danish M.L., Aoki-Ogata H., Amano M., Ide K., Das D., Koh Y., Mitsuya H. Loss of the protease dimerization inhibition activity of tipranavir (TPV) and its association with the acquisition of resistance to TPV by HIV-1. J. Virol. 2012;86(24):13384–13396. doi: 10.1128/jvi.07234-11. PubMed DOI PMC

Arabi Y.M., Gordon A.C., Derde L.P.G., Nichol A.D., Murthy S., Beidh F.A., Annane D., Swaidan L.A., Beane A., Beasley R., Berry L.R., Bhimani Z., Bonten M.J.M., Bradbury C.A., Brunkhorst F.M., Buxton M., Buzgau A., Cheng A., De Jong M., Detry M.A., Duffy E.J., Estcourt L.J., Fitzgerald M., Fowler R., Girard T.D., Goligher E.C., Goossens H., Haniffa R., Higgins A.M., Hills T.E., Horvat C.M., Huang D.T., King A.J., Lamontagne F., Lawler P.R., Lewis R., Linstrum K., Litton E., Lorenzi E., Malakouti S., McAuley D.F., McGlothlin A., McGuinness S., McVerry B.J., Montgomery S.K., Morpeth S.C., Mouncey P.R., Orr K., Parke R., Parker J.C., Patanwala A.E., Rowan K.M., Santos M.S., Saunders C.T., Seymour C.W., Shankar-Hari M., Tong S.Y.C., Turgeon A.F., Turner A.M., Van de Veerdonk F.L., Zarychanski R., Green C., Berry S., Marshall J.C., McArthur C., Angus D.C., Webb S.A. Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial. Intensive Care Med. 2021;47(8):867–886. doi: 10.1007/s00134-021-06448-5. PubMed DOI PMC

Arasappan A., Bennett F., Bogen S.L., Venkatraman S., Blackman M., Chen K.X., Hendrata S., Huang Y., Huelgas R.M., Nair L., Padilla A.I., Pan W., Pike R., Pinto P., Ruan S., Sannigrahi M., Velazquez F., Vibulbhan B., Wu W., Yang W., Saksena A.K., Girijavallabhan V., Shih N.Y., Kong J., Meng T., Jin Y., Wong J., McNamara P., Prongay A., Madison V., Piwinski J.J., Cheng K.C., Morrison R., Malcolm B., Tong X., Ralston R., Njoroge F.G. Discovery of narlaprevir (SCH 900518): a potent, second generation HCV NS3 serine protease inhibitor. ACS Med. Chem. Lett. 2010;1(2):64–69. doi: 10.1021/ml9000276. PubMed DOI PMC

Armstrong L.A., Lange S.M., Dee Cesare V., Matthews S.P., Nirujogi R.S., Cole I., Hope A., Cunningham F., Toth R., Mukherjee R., Bojkova D., Gruber F., Gray D., Wyatt P.G., Cinatl J., Dikic I., Davies P., Kulathu Y. Biochemical characterization of protease activity of Nsp3 from SARS-CoV-2 and its inhibition by nanobodies. PLoS One. 2021;16(7) doi: 10.1371/journal.pone.0253364. PubMed DOI PMC

Arya R., Kumari S., Pandey B., Mistry H., Bihani S.C., Das A., Prashar V., Gupta G.D., Panicker L., Kumar M. Structural insights into SARS-CoV-2 proteins. J. Mol. Biol. 2021;433(2) doi: 10.1016/j.jmb.2020.11.024. PubMed DOI PMC

Atluri K., Aimlin I., Arora S. Current effective therapeutics in management of COVID-19. J. Clin. Med. 2022;11(13) doi: 10.3390/jcm11133838. PubMed DOI PMC

Bacinschi X., Popescu G.C., Zgura A., Gales L., Rodica A., Mercan A., Serban D., Haineala B., Toma L., Iliescu L. A real-world study to compare the safety and efficacy of paritaprevir/ombitasvir/ritonavir and dasabuvir, with or without ribavirin, in 587 patients with chronic hepatitis C at the fundeni clinical Institute, bucharest, Romania. Med. Sci. Mon. Int. Med. J. Exp. Clin. Res. 2022;28 doi: 10.12659/msm.936706. PubMed DOI PMC

Badierah R.A., Uversky V.N., Redwan E.M. Dancing with Trojan horses: an interplay between the extracellular vesicles and viruses. J. Biomol. Struct. Dyn. 2021;39(8):3034–3060. doi: 10.1080/07391102.2020.1756409. PubMed DOI

Bafna K., White K., Harish B., Rosales R., Ramelot T.A., Acton T.B., Moreno E., Kehrer T., Miorin L., Royer C.A., García-Sastre A., Krug R.M., Montelione G.T. Hepatitis C virus drugs that inhibit SARS-CoV-2 papain-like protease synergize with remdesivir to suppress viral replication in cell culture. Cell Rep. 2021;35(7) doi: 10.1016/j.celrep.2021.109133. PubMed DOI PMC

Baker J.D., Uhrich R.L., Kraemer G.C., Love J.E., Kraemer B.C. A drug repurposing screen identifies hepatitis C antivirals as inhibitors of the SARS-CoV2 main protease. PLoS One. 2021;16(2) doi: 10.1371/journal.pone.0245962. PubMed DOI PMC

Bar-On Y.M., Flamholz A., Phillips R., Milo R. SARS-CoV-2 (COVID-19) by the numbers. Elife. 2020;9 doi: 10.7554/eLife.57309. PubMed DOI PMC

Barillari G., Monini P., Sgadari C., Ensoli B. The impact of human papilloma viruses, matrix metallo-proteinases and HIV protease inhibitors on the onset and progression of uterine cervix epithelial tumors: a review of preclinical and clinical studies. Int. J. Mol. Sci. 2018;19(5) doi: 10.3390/ijms19051418. PubMed DOI PMC

Barré-Sinoussi F., Chermann J.C., Rey F., Nugeyre M.T., Chamaret S., Gruest J., Dauguet C., Axler-Blin C., Vézinet-Brun F., Rouzioux C., Rozenbaum W., Montagnier L. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS) Science. 1983;220(4599):868–871. doi: 10.1126/science.6189183. PubMed DOI

Batman G., Oliver A.W., Zehbe I., Richard C., Hampson L., Hampson I.N. Lopinavir up-regulates expression of the antiviral protein ribonuclease L in human papillomavirus-positive cervical carcinoma cells. Antivir. Ther. 2011;16(4):515–525. doi: 10.3851/imp1786. PubMed DOI

Bean B. Antiviral therapy: current concepts and practices. Clin. Microbiol. Rev. 1992;5(2):146–182. doi: 10.1128/cmr.5.2.146. PubMed DOI PMC

Behnam M.A.M., Klein C.D. On track to tackle dengue: history and future of NS4B ligands. Cell Host Microbe. 2021;29(12):1735–1737. doi: 10.1016/j.chom.2021.11.010. PubMed DOI

Behnam M.A.M., Klein C.D. Corona versus dengue: distinct mechanisms for inhibition of polyprotein processing by antiviral drugs. ACS Pharmacol Transl Sci. 2022;5(7):508–511. doi: 10.1021/acsptsci.2c00105. PubMed DOI PMC

Bhatt P.R., Scaiola A., Loughran G., Leibundgut M., Kratzel A., Meurs R., Dreos R., O'Connor K.M., McMillan A., Bode J.W., Thiel V., Gatfield D., Atkins J.F., Ban N. Structural basis of ribosomal frameshifting during translation of the SARS-CoV-2 RNA genome. Science. 2021;372(6548):1306–1313. doi: 10.1126/science.abf3546. PubMed DOI PMC

Bissinger R., Waibel S., Lang F. Induction of suicidal erythrocyte death by nelfinavir. Toxins. 2015;7(5):1616–1628. doi: 10.3390/toxins7051616. PubMed DOI PMC

Blanquart F., Grabowski M.K., Herbeck J., Nalugoda F., Serwadda D., Eller M.A., Robb M.L., Gray R., Kigozi G., Laeyendecker O., Lythgoe K.A., Nakigozi G., Quinn T.C., Reynolds S.J., Wawer M.J., Fraser C. A transmission-virulence evolutionary trade-off explains attenuation of HIV-1 in Uganda. Elife. 2016;5 doi: 10.7554/eLife.20492. PubMed DOI PMC

Boesecke C., Cooper D.A. Toxicity of HIV protease inhibitors: clinical considerations. Curr. Opin. HIV AIDS. 2008;3(6):653–659. doi: 10.1097/COH.0b013e328312c392. PubMed DOI

Boike L., Henning N.J., Nomura D.K. Advances in covalent drug discovery. Nat. Rev. Drug Discov. 2022:1–18. doi: 10.1038/s41573-022-00542-z. PubMed DOI PMC

Bold G., Fässler A., Capraro H.G., Cozens R., Klimkait T., Lazdins J., Mestan J., Poncioni B., Rösel J., Stover D., Tintelnot-Blomley M., Acemoglu F., Beck W., Boss E., Eschbach M., Hürlimann T., Masso E., Roussel S., Ucci-Stoll K., Wyss D., Lang M. New aza-dipeptide analogues as potent and orally absorbed HIV-1 protease inhibitors: candidates for clinical development. J. Med. Chem. 1998;41(18):3387–3401. doi: 10.1021/jm970873c. PubMed DOI

Boonma T., Nutho B., Rungrotmongkol T., Nunthaboot N. Understanding of the drug resistance mechanism of hepatitis C virus NS3/4A to paritaprevir due to D168N/Y mutations: a molecular dynamics simulation perspective. Comput. Biol. Chem. 2019;83 doi: 10.1016/j.compbiolchem.2019.107154. PubMed DOI

Boras B., Jones R.M., Anson B.J., Arenson D., Aschenbrenner L., Bakowski M.A., Beutler N., Binder J., Chen E., Eng H., Hammond H., Hammond J., Haupt R.E., Hoffman R., Kadar E.P., Kania R., Kimoto E., Kirkpatrick M.G., Lanyon L., Lendy E.K., Lillis J.R., Logue J., Luthra S.A., Ma C., Mason S.W., McGrath M.E., Noell S., Obach R.S., Mn O.B., O'Connor R., Ogilvie K., Owen D., Pettersson M., Reese M.R., Rogers T.F., Rosales R., Rossulek M.I., Sathish J.G., Shirai N., Steppan C., Ticehurst M., Updyke L.W., Weston S., Zhu Y., White K.M., García-Sastre A., Wang J., Chatterjee A.K., Mesecar A.D., Frieman M.B., Anderson A.S., Allerton C. Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19. Nat. Commun. 2021;12(1):6055. doi: 10.1038/s41467-021-26239-2. PubMed DOI PMC

Borowiec B.M., Angelova Volponi A., Mozdziak P., Kempisty B., Dyszkiewicz-Konwińska M. Small extracellular vesicles and COVID19-using the "trojan horse" to tackle the giant. Cells. 2021;10(12) doi: 10.3390/cells10123383. PubMed DOI PMC

Broder S. The development of antiretroviral therapy and its impact on the HIV-1/AIDS pandemic. Antivir. Res. 2010;85(1):1–18. doi: 10.1016/j.antiviral.2009.10.002. PubMed DOI PMC

Brüning A., Friese K., Burges A., Mylonas I. Tamoxifen enhances the cytotoxic effects of nelfinavir in breast cancer cells. Breast Cancer Res. 2010;12(4):R45. doi: 10.1186/bcr2602. PubMed DOI PMC

Buitrón-González I., Aguilera-Durán G., Romo-Mancillas A. In-silico drug repurposing study: amprenavir, enalaprilat, and plerixafor, potential drugs for destabilizing the SARS-CoV-2 S-protein-angiotensin-converting enzyme 2 complex. Results Chem. 2021;3 doi: 10.1016/j.rechem.2020.100094. PubMed DOI PMC

Bunge E.M., Hoet B., Chen L., Lienert F., Weidenthaler H., Baer L.R., Steffen R. The changing epidemiology of human monkeypox-A potential threat? A systematic review. PLoS Neglected Trop. Dis. 2022;16(2) doi: 10.1371/journal.pntd.0010141. PubMed DOI PMC

Burki T. The future of Paxlovid for COVID-19. Lancet Respir. Med. 2022;10(7):e68. doi: 10.1016/s2213-2600(22)00192-8. PubMed DOI PMC

Busti A.J., Hall R.G., Margolis D.M. Atazanavir for the treatment of human immunodeficiency virus infection. Pharmacotherapy. 2004;24(12):1732–1747. doi: 10.1592/phco.24.17.1732.52347. PubMed DOI

Callaway E. The coronavirus is mutating - does it matter? Nature. 2020;585(7824):174–177. doi: 10.1038/d41586-020-02544-6. PubMed DOI

Cao B., Wang Y., Wen D., Liu W., Wang J., Fan G., Ruan L., Song B., Cai Y., Wei M., Li X., Xia J., Chen N., Xiang J., Yu T., Bai T., Xie X., Zhang L., Li C., Yuan Y., Chen H., Li H., Huang H., Tu S., Gong F., Liu Y., Wei Y., Dong C., Zhou F., Gu X., Xu J., Liu Z., Zhang Y., Li H., Shang L., Wang K., Li K., Zhou X., Dong X., Qu Z., Lu S., Hu X., Ruan S., Luo S., Wu J., Peng L., Cheng F., Pan L., Zou J., Jia C., Wang J., Liu X., Wang S., Wu X., Ge Q., He J., Zhan H., Qiu F., Guo L., Huang C., Jaki T., Hayden F.G., Horby P.W., Zhang D., Wang C. A trial of lopinavir–ritonavir in adults hospitalized with severe covid-19. N. Engl. J. Med. 2020;382(19):1787–1799. doi: 10.1056/NEJMoa2001282. PubMed DOI PMC

Carlin A.F., Clark A.E., Chaillon A., Garretson A.F., Bray W., Porrachia M., Santos A.T., Rana T.M., Smith D.M. Virologic and immunologic characterization of COVID-19 recrudescence after nirmatrelvir/ritonavir treatment. Clin. Infect. Dis. 2022 doi: 10.1093/cid/ciac496. PubMed DOI PMC

Cervino L., Hynicka L.M. Direct-acting antivirals to prevent vertical transmission of viral hepatitis C: when is the optimal time to treat? Ann. Pharmacother. 2018;52(11):1152–1157. doi: 10.1177/1060028018772181. PubMed DOI

Champenois K., Baras A., Choisy P., Ajana F., Melliez H., Bocket L., Yazdanpanah Y. Lopinavir/ritonavir resistance in patients infected with HIV-1: two divergent resistance pathways? J. Med. Virol. 2011;83(10):1677–1681. doi: 10.1002/jmv.22161. PubMed DOI

Chang M.W., Torbett B.E. Accessory mutations maintain stability in drug-resistant HIV-1 protease. J. Mol. Biol. 2011;410(4):756–760. doi: 10.1016/j.jmb.2011.03.038. PubMed DOI PMC

Chen C.-H., Chen C.-H., Lin C.-L., Lin C.-Y., Hu T.-H., Tung S.-Y., Hsieh S.-Y., Lu S.-N., Chien R.-N., Hung C.-H., Sheen I.S. Real-world safety and efficacy of paritaprevir/ritonavir/ombitasvir plus dasabuvir ± ribavirin in patients with hepatitis C virus genotype 1 and advanced hepatic fibrosis or compensated cirrhosis: a multicenter pooled analysis. Sci. Rep. 2019;9(1):7086. doi: 10.1038/s41598-019-43554-3. PubMed DOI PMC

Chia C.S.B., Xu W., Shuyi Ng P. A patent review on SARS coronavirus main protease (3CL(pro)) inhibitors. ChemMedChem. 2022;17(1) doi: 10.1002/cmdc.202100576. e202100576. PubMed DOI PMC

Chow W.A., Guo S., Valdes-Albini F. Nelfinavir induces liposarcoma apoptosis and cell cycle arrest by upregulating sterol regulatory element binding protein-1. Anti Cancer Drugs. 2006;17(8):891–903. doi: 10.1097/01.cad.0000224448.08706.76. PubMed DOI

Chuck C.P., Chen C., Ke Z., Wan D.C., Chow H.F., Wong K.B. Design, synthesis and crystallographic analysis of nitrile-based broad-spectrum peptidomimetic inhibitors for coronavirus 3C-like proteases. Eur. J. Med. Chem. 2013;59:1–6. doi: 10.1016/j.ejmech.2012.10.053. PubMed DOI PMC

Chun T.W., Finzi D., Margolick J., Chadwick K., Schwartz D., Siliciano R.F. In vivo fate of HIV-1-infected T cells: quantitative analysis of the transition to stable latency. Nat. Med. 1995;1(12):1284–1290. doi: 10.1038/nm1295-1284. PubMed DOI

Churchill S.A. Protease inhibitors: implications for HIV research and treatment. J. Int. Assoc. Phys. AIDS Care. 1996;2(1):13–18. PubMed

Clavel F., Guétard D., Brun-Vézinet F., Chamaret S., Rey M.A., Santos-Ferreira M.O., Laurent A.G., Dauguet C., Katlama C., Rouzioux C., et al. Isolation of a new human retrovirus from West African patients with AIDS. Science. 1986;233(4761):343–346. doi: 10.1126/science.2425430. PubMed DOI

Constant D.A., Mateo R., Nagamine C.M., Kirkegaard K. Targeting intramolecular proteinase NS2B/3 cleavages for trans-dominant inhibition of dengue virus. Proc. Natl. Acad. Sci. U. S. A. 2018;115(40):10136–10141. doi: 10.1073/pnas.1805195115. PubMed DOI PMC

Corman V.M., Muth D., Niemeyer D., Drosten C. Hosts and sources of endemic human coronaviruses. Adv. Virus Res. 2018;100:163–188. doi: 10.1016/bs.aivir.2018.01.001. PubMed DOI PMC

Cotter T.G., Jensen D.M. Glecaprevir/pibrentasvir for the treatment of chronic hepatitis C: design, development, and place in therapy. Drug Des. Dev. Ther. 2019;13:2565–2577. doi: 10.2147/dddt.S172512. PubMed DOI PMC

Coulson J.M., Adams A., Gray L.A., Evans A. COVID-19 "Rebound" associated with nirmatrelvir/ritonavir pre-hospital therapy. J. Infect. 2022 doi: 10.1016/j.jinf.2022.06.011. PubMed DOI PMC

Couzin-Frankel J. Antiviral pills could change pandemic's course. Science. 2021;374(6569):799–800. doi: 10.1126/science.acx9605. PubMed DOI

Craig J.C., Duncan I.B., Hockley D., Grief C., Roberts N.A., Mills J.S. Antiviral properties of Ro 31-8959, an inhibitor of human immunodeficiency virus (HIV) proteinase. Antivir. Res. 1991;16(4):295–305. doi: 10.1016/0166-3542(91)90045-s. PubMed DOI

Cuevas J.M., González-Candelas F., Moya A., Sanjuán R. Effect of ribavirin on the mutation rate and spectrum of hepatitis C virus in vivo. J. Virol. 2009;83(11):5760–5764. doi: 10.1128/jvi.00201-09. PubMed DOI PMC

Cully M. A tale of two antiviral targets - and the COVID-19 drugs that bind them. Nat. Rev. Drug Discov. 2022;21(1):3–5. doi: 10.1038/d41573-021-00202-8. PubMed DOI

da Costa V.G., Moreli M.L., Saivish M.V. The emergence of SARS, MERS and novel SARS-2 coronaviruses in the 21st century. Arch. Virol. 2020;165(7):1517–1526. doi: 10.1007/s00705-020-04628-0. PubMed DOI PMC

da Silva Rocha S.F.L., Olanda C.G., Fokoue H.H., Sant'Anna C.M.R. Virtual screening techniques in drug discovery: review and recent applications. Curr. Top. Med. Chem. 2019;19(19):1751–1767. doi: 10.2174/1568026619666190816101948. PubMed DOI

Dash P.K., Kaminski R., Bella R., Su H., Mathews S., Ahooyi T.M., Chen C., Mancuso P., Sariyer R., Ferrante P., Donadoni M., Robinson J.A., Sillman B., Lin Z., Hilaire J.R., Banoub M., Elango M., Gautam N., Mosley R.L., Poluektova L.Y., McMillan J., Bade A.N., Gorantla S., Sariyer I.K., Burdo T.H., Young W.B., Amini S., Gordon J., Jacobson J.M., Edagwa B., Khalili K., Gendelman H.E. Sequential LASER ART and CRISPR treatments eliminate HIV-1 in a subset of infected humanized mice. Nat. Commun. 2019;10(1):2753. doi: 10.1038/s41467-019-10366-y. PubMed DOI PMC

Davis D.A., Soule E.E., Davidoff K.S., Daniels S.I., Naiman N.E., Yarchoan R. Activity of human immunodeficiency virus type 1 protease inhibitors against the initial autocleavage in Gag-Pol polyprotein processing. Antimicrob. Agents Chemother. 2012;56(7):3620–3628. doi: 10.1128/AAC.00055-12. PubMed DOI PMC

De Clercq E. Perspectives for the chemotherapy of AIDS. Anticancer Res. 1987;7(5b):1023–1038. PubMed

De Clercq E. Antiviral drugs in current clinical use. J. Clin. Virol. 2004;30(2):115–133. doi: 10.1016/j.jcv.2004.02.009. PubMed DOI

De Clercq E., Li G. Approved antiviral drugs over the past 50 years. Clin. Microbiol. Rev. 2016;29(3):695–747. doi: 10.1128/CMR.00102-15. PubMed DOI PMC

de Mendoza C., Valer L., Bacheler L., Pattery T., Corral A., Soriano V. Prevalence of the HIV-1 protease mutation I47A in clinical practice and association with lopinavir resistance. AIDS. 2006;20(7):1071–1074. doi: 10.1097/01.aids.0000222084.44411.cc. PubMed DOI

De Vlaminck I., Khush K.K., Strehl C., Kohli B., Luikart H., Neff N.F., Okamoto J., Snyder T.M., Cornfield D.N., Nicolls M.R., Weill D., Bernstein D., Valantine H.A., Quake S.R. Temporal response of the human virome to immunosuppression and antiviral therapy. Cell. 2013;155(5):1178–1187. doi: 10.1016/j.cell.2013.10.034. PubMed DOI PMC

de Wit E., Feldmann F., Cronin J., Jordan R., Okumura A., Thomas T., Scott D., Cihlar T., Feldmann H. Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc. Natl. Acad. Sci. U. S. A. 2020;117(12):6771–6776. doi: 10.1073/pnas.1922083117. PubMed DOI PMC

Deng W., Baki L., Yin J., Zhou H., Baumgarten C.M. HIV protease inhibitors elicit volume-sensitive Cl- current in cardiac myocytes via mitochondrial ROS. J. Mol. Cell. Cardiol. 2010;49(5):746–752. doi: 10.1016/j.yjmcc.2010.08.013. PubMed DOI PMC

Denison M.R., Graham R.L., Donaldson E.F., Eckerle L.D., Baric R.S. Coronaviruses: an RNA proofreading machine regulates replication fidelity and diversity. RNA Biol. 2011;8(2):270–279. doi: 10.4161/rna.8.2.15013. PubMed DOI PMC

Dienstag J.L. In: Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. eighth ed. Bennett J.E., Dolin R., Blaser M.J., editors. W.B. Saunders; Philadelphia: 2015. 46 - antiviral drugs against hepatitis viruses; pp. 563–575. e563.

Doyon L., Tremblay S., Bourgon L., Wardrop E., Cordingley M.G. Selection and characterization of HIV-1 showing reduced susceptibility to the non-peptidic protease inhibitor tipranavir. Antivir. Res. 2005;68(1):27–35. doi: 10.1016/j.antiviral.2005.07.003. PubMed DOI

Dragovich P.S., Prins T.J., Zhou R., Webber S.E., Marakovits J.T., Fuhrman S.A., Patick A.K., Matthews D.A., Lee C.A., Ford C.E., Burke B.J., Rejto P.A., Hendrickson T.F., Tuntland T., Brown E.L., Meador J.W., 3rd, Ferre R.A., Harr J.E., Kosa M.B., Worland S.T. Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 4. Incorporation of P1 lactam moieties as L-glutamine replacements. J. Med. Chem. 1999;42(7):1213–1224. doi: 10.1021/jm9805384. PubMed DOI

Dunning J., Thwaites R.S., Openshaw P.J.M. Seasonal and pandemic influenza: 100 years of progress, still much to learn. Mucosal Immunol. 2020;13(4):566–573. doi: 10.1038/s41385-020-0287-5. PubMed DOI PMC

Dustin L.B., Bartolini B., Capobianchi M.R., Pistello M. Hepatitis C virus: life cycle in cells, infection and host response, and analysis of molecular markers influencing the outcome of infection and response to therapy. Clin. Microbiol. Infect. 2016;22(10):826–832. doi: 10.1016/j.cmi.2016.08.025. PubMed DOI PMC

El-Baba T.J., Lutomski C.A., Kantsadi A.L., Malla T.R., John T., Mikhailov V., Bolla J.R., Schofield C.J., Zitzmann N., Vakonakis I., Robinson C.V. Allosteric inhibition of the SARS-CoV-2 main protease: insights from mass spectrometry based assays. Angew Chem. Int. Ed. Engl. 2020;59(52):23544–23548. doi: 10.1002/anie.202010316. PubMed DOI PMC

Elion G.B., Furman P.A., Fyfe J.A., de Miranda P., Beauchamp L., Schaeffer H.J. Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl) guanine. Proc. Natl. Acad. Sci. U. S. A. 1977;74(12):5716–5720. doi: 10.1073/pnas.74.12.5716. PubMed DOI PMC

Elion R., Cohen C., Gathe J., Shalit P., Hawkins T., Liu H.C., Mathias A.A., Chuck S.L., Kearney B.P., Warren D.R. Phase 2 study of cobicistat versus ritonavir each with once-daily atazanavir and fixed-dose emtricitabine/tenofovir df in the initial treatment of HIV infection. Aids. 2011;25(15):1881–1886. doi: 10.1097/QAD.0b013e32834b4d48. PubMed DOI

Ely E.W., Ramanan A.V., Kartman C.E., de Bono S., Liao R., Piruzeli M.L.B., Goldman J.D., Saraiva J.F.K., Chakladar S., Marconi V.C. Efficacy and safety of baricitinib plus standard of care for the treatment of critically ill hospitalised adults with COVID-19 on invasive mechanical ventilation or extracorporeal membrane oxygenation: an exploratory, randomised, placebo-controlled trial. Lancet Respir. Med. 2022 doi: 10.1016/s2213-2600(22)00006-6. PubMed DOI PMC

Erbel P., Schiering N., D'Arcy A., Renatus M., Kroemer M., Lim S.P., Yin Z., Keller T.H., Vasudevan S.G., Hommel U. Structural basis for the activation of flaviviral NS3 proteases from dengue and West Nile virus. Nat. Struct. Mol. Biol. 2006;13(4):372–373. doi: 10.1038/nsmb1073. PubMed DOI

Evenseth L.S.M., Gabrielsen M., Sylte I. The GABA(B) receptor-structure, ligand binding and drug development. Molecules. 2020;25(13) doi: 10.3390/molecules25133093. PubMed DOI PMC

Excision https://www.excision.bio/technology

Fassmannová D., Sedlák F., Sedláček J., Špička I., Grantz Šašková K. Nelfinavir inhibits the TCF11/nrf1-mediated proteasome recovery pathway in multiple myeloma. Cancers. 2020;12(5) doi: 10.3390/cancers12051065. PubMed DOI PMC

Foote B.S., Spooner L.M., Belliveau P.P. Boceprevir: a protease inhibitor for the treatment of chronic hepatitis C. Ann. Pharmacother. 2011;45(9):1085–1093. doi: 10.1345/aph.1P744. PubMed DOI

Fu L., Ye F., Feng Y., Yu F., Wang Q., Wu Y., Zhao C., Sun H., Huang B., Niu P., Song H., Shi Y., Li X., Tan W., Qi J., Gao G.F. Both Boceprevir and GC376 efficaciously inhibit SARS-CoV-2 by targeting its main protease. Nat. Commun. 2020;11(1):4417. doi: 10.1038/s41467-020-18233-x. PubMed DOI PMC

Furfine E.S., Baker C.T., Hale M.R., Reynolds D.J., Salisbury J.A., Searle A.D., Studenberg S.D., Todd D., Tung R.D., Spaltenstein A. Preclinical pharmacology and pharmacokinetics of GW433908, a water-soluble prodrug of the human immunodeficiency virus protease inhibitor amprenavir. Antimicrob. Agents Chemother. 2004;48(3):791–798. doi: 10.1128/aac.48.3.791-798.2004. PubMed DOI PMC

Furman P.A., de Miranda P., St Clair M.H., Elion G.B. Metabolism of acyclovir in virus-infected and uninfected cells. Antimicrob. Agents Chemother. 1981;20(4):518–524. doi: 10.1128/aac.20.4.518. PubMed DOI PMC

Gable J.E., Lee G.M., Acker T.M., Hulce K.R., Gonzalez E.R., Schweigler P., Melkko S., Farady C.J., Craik C.S. Fragment-based protein-protein interaction antagonists of a viral dimeric protease. ChemMedChem. 2016;11(8):862–869. doi: 10.1002/cmdc.201500526. PubMed DOI PMC

Gallo R.C., Poiesz B.J., Ruscetti F.W. Regulation of human T-cell proliferation: T-cell growth factor and isolation of a new class of type-C retroviruses from human T-cells. Haematol. Blood Transfus. 1981;26:502–514. doi: 10.1007/978-3-642-67984-1_93. PubMed DOI

Gallo R.C., Sarin P.S., Gelmann E.P., Robert-Guroff M., Richardson E., Kalyanaraman V.S., Mann D., Sidhu G.D., Stahl R.E., Zolla-Pazner S., Leibowitch J., Popovic M. Isolation of human T-cell leukemia virus in acquired immune deficiency syndrome (AIDS) Science. 1983;220(4599):865–867. doi: 10.1126/science.6601823. PubMed DOI

Gan J.H., Liu J.X., Liu Y., Chen S.W., Dai W.T., Xiao Z.X., Cao Y. DrugRep: an automatic virtual screening server for drug repurposing. Acta Pharmacol. Sin. 2022;1–9 doi: 10.1038/s41401-022-00996-2. PubMed DOI PMC

Gane E., Poordad F., Wang S., Asatryan A., Kwo P.Y., Lalezari J., Wyles D.L., Hassanein T., Aguilar H., Maliakkal B., Liu R., Lin C.W., Ng T.I., Kort J., Mensa F.J. High efficacy of ABT-493 and ABT-530 treatment in patients with HCV genotype 1 or 3 infection and compensated cirrhosis. Gastroenterology. 2016;151(4):651–659. doi: 10.1053/j.gastro.2016.07.020. e651. PubMed DOI

Gane E.J., Kowdley K.V., Pound D., Stedman C.A., Davis M., Etzkorn K., Gordon S.C., Bernstein D., Everson G., Rodriguez-Torres M., Tsai N., Khalid O., Yang J.C., Lu S., Dvory-Sobol H., Stamm L.M., Brainard D.M., McHutchison J.G., Tong M., Chung R.T., Beavers K., Poulos J.E., Kwo P.Y., Nguyen M.H. Efficacy of sofosbuvir, velpatasvir, and GS-9857 in patients with hepatitis C virus genotype 2, 3, 4, or 6 infections in an open-label, phase 2 trial. Gastroenterology. 2016;151(5):902–909. doi: 10.1053/j.gastro.2016.07.038. PubMed DOI

Gane E.J., Schwabe C., Hyland R.H., Yang Y., Svarovskaia E., Stamm L.M., Brainard D.M., McHutchison J.G., Stedman C.A. Efficacy of the combination of sofosbuvir, velpatasvir, and the NS3/4A protease inhibitor GS-9857 in treatment-naïve or previously treated patients with hepatitis C virus genotype 1 or 3 infections. Gastroenterology. 2016;151(3):448–456. doi: 10.1053/j.gastro.2016.05.021. e441. PubMed DOI

Garcia-Cehic D., Rando A., Rodriguez-Frias F., Gregori J., Costa J.G., Carrión J.A., Macenlle R., Pamplona J., Castro-Iglesias A., Cañizares A., Tabernero D., Campos C., Buti M., Esteban J.I., Quer J. Resistance-associated substitutions after sofosbuvir/velpatasvir/voxilaprevir triple therapy failure. J. Viral Hepat. 2021;28(9):1319–1324. doi: 10.1111/jvh.13497. PubMed DOI

Gehlhaar D.K., Verkhivker G.M., Rejto P.A., Sherman C.J., Fogel D.B., Fogel L.J., Freer S.T. Molecular recognition of the inhibitor AG-1343 by HIV-1 protease: conformationally flexible docking by evolutionary programming. Chem. Biol. 1995;2(5):317–324. doi: 10.1016/1074-5521(95)90050-0. PubMed DOI

Geller R., Estada Ú., Peris J.B., Andreu I., Bou J.V., Garijo R., Cuevas J.M., Sabariegos R., Mas A., Sanjuán R. Highly heterogeneous mutation rates in the hepatitis C virus genome. Nat. Microbiol. 2016;1(7) doi: 10.1038/nmicrobiol.2016.45. PubMed DOI

Georgi F., Andriasyan V., Witte R., Murer L., Hemmi S., Yu L., Grove M., Meili N., Kuttler F., Yakimovich A., Turcatti G., Greber U.F. The FDA-approved drug nelfinavir inhibits lytic cell-free but not cell-associated nonlytic transmission of human adenovirus. Antimicrob. Agents Chemother. 2020;64(9) doi: 10.1128/AAC.01002-20. e01002-01020. PubMed DOI PMC

Ghosh A.K., Dawson Z.L., Mitsuya H. Darunavir, a conceptually new HIV-1 protease inhibitor for the treatment of drug-resistant HIV. Bioorg. Med. Chem. 2007;15(24):7576–7580. doi: 10.1016/j.bmc.2007.09.010. PubMed DOI PMC

Ghosh A.K., Chapsal B.D., Weber I.T., Mitsuya H. Design of HIV protease inhibitors targeting protein backbone: an effective strategy for combating drug resistance. Acc. Chem. Res. 2008;41(1):78–86. doi: 10.1021/ar7001232. PubMed DOI

Ghosh A.K., Osswald H.L., Prato G. Recent progress in the development of HIV-1 protease inhibitors for the treatment of HIV/AIDS. J. Med. Chem. 2016;59(11):5172–5208. doi: 10.1021/acs.jmedchem.5b01697. PubMed DOI PMC

Gillis E.P., Eastman K.J., Hill M.D., Donnelly D.J., Meanwell N.A. Applications of fluorine in medicinal chemistry. J. Med. Chem. 2015;58(21):8315–8359. doi: 10.1021/acs.jmedchem.5b00258. PubMed DOI

Gills J.J., Lopiccolo J., Dennis P.A. Nelfinavir, a new anti-cancer drug with pleiotropic effects and many paths to autophagy. Autophagy. 2008;4(1):107–109. doi: 10.4161/auto.5224. PubMed DOI

Goldsmith D.R., Perry C.M. Atazanavir. Drugs. 2003;63(16):1679–1693. doi: 10.2165/00003495-200363160-00003. discussion 1694-1675. PubMed DOI

Gordon S.C., Muir A.J., Lim J.K., Pearlman B., Argo C.K., Ramani A., Maliakkal B., Alam I., Stewart T.G., Vainorius M., Peter J., Nelson D.R., Fried M.W., Reddy K.R. Safety profile of boceprevir and telaprevir in chronic hepatitis C: real world experience from HCV-TARGET. J. Hepatol. 2015;62(2):286–293. doi: 10.1016/j.jhep.2014.08.052. PubMed DOI PMC

Graff D.E., Shakhnovich E.I., Coley C.W. Accelerating high-throughput virtual screening through molecular pool-based active learning. Chem. Sci. 2021;12(22):7866–7881. doi: 10.1039/d0sc06805e. PubMed DOI PMC

Graham S.V. The human papillomavirus replication cycle, and its links to cancer progression: a comprehensive review. Clin. Sci. (Lond.) 2017;131(17):2201–2221. doi: 10.1042/cs20160786. PubMed DOI

Grandi N., Tramontano E. Human endogenous retroviruses are ancient acquired elements still shaping innate immune responses. Front. Immunol. 2018;9(2039) doi: 10.3389/fimmu.2018.02039. PubMed DOI PMC

Greasley S.E., Noell S., Plotnikova O., Ferre R., Liu W., Bolanos B., Fennell K., Nicki J., Craig T., Zhu Y., Stewart A.E., Steppan C.M. Structural basis for the in vitro efficacy of nirmatrelvir against SARS-CoV-2 variants. J. Biol. Chem. 2022;298(6) doi: 10.1016/j.jbc.2022.101972. PubMed DOI PMC

Gu Y., Wang X., Wang Y., Wang Y., Li J., Yu F.X. Nelfinavir inhibits human DDI2 and potentiates cytotoxicity of proteasome inhibitors. Cell. Signal. 2020;75 doi: 10.1016/j.cellsig.2020.109775. PubMed DOI

Hahm B., Han D.S., Back S.H., Song O.K., Cho M.J., Kim C.J., Shimotohno K., Jang S.K. NS3-4A of hepatitis C virus is a chymotrypsin-like protease. J. Virol. 1995;69(4):2534–2539. doi: 10.1128/jvi.69.4.2534-2539.1995. PubMed DOI PMC

Hakkola J., Hukkanen J., Turpeinen M., Pelkonen O. Inhibition and induction of CYP enzymes in humans: an update. Arch. Toxicol. 2020;94(11):3671–3722. doi: 10.1007/s00204-020-02936-7. PubMed DOI PMC

Hammond J., Leister-Tebbe H., Gardner A., Abreu P., Bao W., Wisemandle W., Baniecki M., Hendrick V.M., Damle B., Simón-Campos A., Pypstra R., Rusnak J.M. Oral nirmatrelvir for high-risk, nonhospitalized adults with covid-19. N. Engl. J. Med. 2022;386(15):1397–1408. doi: 10.1056/NEJMoa2118542. PubMed DOI PMC

Han D.S., Hahm B., Rho H.M., Jang S.K. Identification of the protease domain in NS3 of hepatitis C virus. J. Gen. Virol. 1995;76(Pt 4):985–993. doi: 10.1099/0022-1317-76-4-985. PubMed DOI

Han B., Martin R., Xu S., Parvangada A., Svarovskaia E.S., Mo H., Dvory-Sobol H. Sofosbuvir susceptibility of genotype 1 to 6 HCV from DAA-naïve subjects. Antivir. Res. 2019;170 doi: 10.1016/j.antiviral.2019.104574. PubMed DOI

Han S.H., Goins C.M., Arya T., Shin W.J., Maw J., Hooper A., Sonawane D.P., Porter M.R., Bannister B.E., Crouch R.D., Lindsey A.A., Lakatos G., Martinez S.R., Alvarado J., Akers W.S., Wang N.S., Jung J.U., Macdonald J.D., Stauffer S.R. Structure-based optimization of ml300-derived, noncovalent inhibitors targeting the severe acute respiratory syndrome coronavirus 3CL protease (SARS-CoV-2 3CL(pro)) J. Med. Chem. 2022;65(4):2880–2904. doi: 10.1021/acs.jmedchem.1c00598. PubMed DOI PMC

Harper S., McCauley J.A., Rudd M.T., Ferrara M., DiFilippo M., Crescenzi B., Koch U., Petrocchi A., Holloway M.K., Butcher J.W., Romano J.J., Bush K.J., Gilbert K.F., McIntyre C.J., Nguyen K.T., Nizi E., Carroll S.S., Ludmerer S.W., Burlein C., DiMuzio J.M., Graham D.J., McHale C.M., Stahlhut M.W., Olsen D.B., Monteagudo E., Cianetti S., Giuliano C., Pucci V., Trainor N., Fandozzi C.M., Rowley M., Coleman P.J., Vacca J.P., Summa V., Liverton N.J. Discovery of MK-5172, a macrocyclic hepatitis C virus NS3/4a protease inhibitor. ACS Med. Chem. Lett. 2012;3(4):332–336. doi: 10.1021/ml300017p. PubMed DOI PMC

Hayashi H., Takamune N., Nirasawa T., Aoki M., Morishita Y., Das D., Koh Y., Ghosh A.K., Misumi S., Mitsuya H. Dimerization of HIV-1 protease occurs through two steps relating to the mechanism of protease dimerization inhibition by darunavir. Proc. Natl. Acad. Sci. USA. 2014;111(33):12234–12239. doi: 10.1073/pnas.1400027111. PubMed DOI PMC

Heo Y.A., Deeks E.D. Sofosbuvir/velpatasvir/voxilaprevir: a review in chronic hepatitis C. Drugs. 2018;78(5):577–587. doi: 10.1007/s40265-018-0895-5. PubMed DOI

Hermans P.E., Cockerill F.R., 3rd Antiviral agents. Mayo Clin. Proc. 1983;58(4):217–222. PubMed

Hermida-Matsumoto L., Resh M.D. Human immunodeficiency virus type 1 protease triggers a myristoyl switch that modulates membrane binding of Pr55(gag) and p17MA. J. Virol. 1999;73(3):1902–1908. doi: 10.1128/jvi.73.3.1902-1908.1999. PubMed DOI PMC

Heskin J., Pallett S.J.C., Mughal N., Davies G.W., Moore L.S.P., Rayment M., Jones R. Caution required with use of ritonavir-boosted PF-07321332 in COVID-19 management. Lancet. 2022;399(10319):21–22. doi: 10.1016/S0140-6736(21)02657-X. PubMed DOI PMC

Hézode C. Treatment of hepatitis C: results in real life. Liver Int. 2018;38(Suppl. 1):21–27. doi: 10.1111/liv.13638. PubMed DOI

Hilgenfeld R., Lei J., Zhang L. The structure of the Zika virus protease, NS2B/NS3(pro) Adv. Exp. Med. Biol. 2018;1062:131–145. doi: 10.1007/978-981-10-8727-1_10. PubMed DOI

Ho J.S.Y., Zhu Z., Marazzi I. Unconventional viral gene expression mechanisms as therapeutic targets. Nature. 2021;593(7859):362–371. doi: 10.1038/s41586-021-03511-5. PubMed DOI

Hoffman R.L., Kania R.S., Brothers M.A., Davies J.F., Ferre R.A., Gajiwala K.S., He M., Hogan R.J., Kozminski K., Li L.Y., Lockner J.W., Lou J., Marra M.T., Mitchell L.J., Jr., Murray B.W., Nieman J.A., Noell S., Planken S.P., Rowe T., Ryan K., Smith G.J., 3rd, Solowiej J.E., Steppan C.M., Taggart B. Discovery of ketone-based covalent inhibitors of coronavirus 3CL proteases for the potential therapeutic treatment of COVID-19. J. Med. Chem. 2020;63(21):12725–12747. doi: 10.1021/acs.jmedchem.0c01063. PubMed DOI PMC

Howe A.Y.M., Venkatraman S. The discovery and development of boceprevir: a novel, first-generation inhibitor of the hepatitis C virus NS3/4A serine protease. J. Clin. Transl. Hepatol. 2013;1(1):22–32. doi: 10.14218/JCTH.2013.002XX. PubMed DOI PMC

Huang L., Li L., Tien C., LaBarbera D.V., Chen C. Targeting HIV-1 protease autoprocessing for high-throughput drug discovery and drug resistance assessment. Sci. Rep. 2019;9(1):301. doi: 10.1038/s41598-018-36730-4. PubMed DOI PMC

Hui D.S., E I.A., Madani T.A., Ntoumi F., Kock R., Dar O., Ippolito G., McHugh T.D., Memish Z.A., Drosten C., Zumla A., Petersen E. The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health - the latest 2019 novel coronavirus outbreak in Wuhan, China. Int. J. Infect. Dis. 2020;91:264–266. doi: 10.1016/j.ijid.2020.01.009. PubMed DOI PMC

Humpolíčková J., Weber J., Starková J., Mašínová E., Günterová J., Flaisigová I., Konvalinka J., Majerová T. Inhibition of the precursor and mature forms of HIV-1 protease as a tool for drug evaluation. Sci. Rep. 2018;8(1) doi: 10.1038/s41598-018-28638-w. PubMed DOI PMC

Hwang Y.-C., Lu R.-M., Su S.-C., Chiang P.-Y., Ko S.-H., Ke F.-Y., Liang K.-H., Hsieh T.-Y., Wu H.-C. Monoclonal antibodies for COVID-19 therapy and SARS-CoV-2 detection. J. Biomed. Sci. 2022;29(1):1. doi: 10.1186/s12929-021-00784-w. PubMed DOI PMC

Iketani S., Mohri H., Culbertson B., Hong S.J., Duan Y., Luck M.I., Annavajhala M.K., Guo Y., Sheng Z., Uhlemann A.C., Goff S.P., Sabo Y., Yang H., Chavez A., Ho D.D. Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir. Nature. 2022 doi: 10.1038/s41586-022-05514-2. PubMed DOI PMC

Isken O., Walther T., Wong-Dilworth L., Rehders D., Redecke L., Tautz N. Identification of NS2 determinants stimulating intrinsic HCV NS2 protease activity. PLoS Pathog. 2022;18(6) doi: 10.1371/journal.ppat.1010644. PubMed DOI PMC

Jacks T., Power M.D., Masiarz F.R., Luciw P.A., Barr P.J., Varmus H.E. Characterization of ribosomal frameshifting in HIV-1 gag-pol expression. Nature. 1988;331(6153):280–283. doi: 10.1038/331280a0. PubMed DOI

Jacobs J., Grum-Tokars V., Zhou Y., Turlington M., Saldanha S.A., Chase P., Eggler A., Dawson E.S., Baez-Santos Y.M., Tomar S., Mielech A.M., Baker S.C., Lindsley C.W., Hodder P., Mesecar A., Stauffer S.R. Discovery, synthesis, and structure-based optimization of a series of N-(tert-butyl)-2-(N-arylamido)-2-(pyridin-3-yl) acetamides (ML188) as potent noncovalent small molecule inhibitors of the severe acute respiratory syndrome coronavirus (SARS-CoV) 3CL protease. J. Med. Chem. 2013;56(2):534–546. doi: 10.1021/jm301580n. PubMed DOI PMC

Jacobsen H., Yasargil K., Winslow D.L., Craig J.C., Kröhn A., Duncan I.B., Mous J. Characterization of human immunodeficiency virus type 1 mutantswith decreased sensitivity to proteinase inhibitor Ro 31-8959. Virology. 1995;206(1):527–534. doi: 10.1016/S0042-6822(95)80069-7. PubMed DOI

Jacobson I.M., Lawitz E., Gane E.J., Willems B.E., Ruane P.J., Nahass R.G., Borgia S.M., Shafran S.D., Workowski K.A., Pearlman B., Hyland R.H., Stamm L.M., Svarovskaia E., Dvory-Sobol H., Zhu Y., Subramanian G.M., Brainard D.M., McHutchison J.G., Bräu N., Berg T., Agarwal K., Bhandari B.R., Davis M., Feld J.J., Dore G.J., Stedman C.A.M., Thompson A.J., Asselah T., Roberts S.K., Foster G.R. Efficacy of 8 Weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with chronic HCV infection: 2 phase 3 randomized trials. Gastroenterology. 2017;153(1):113–122. doi: 10.1053/j.gastro.2017.03.047. PubMed DOI

Jacobson I.M., Lawitz E., Kwo P.Y., Hézode C., Peng C.Y., Howe A.Y.M., Hwang P., Wahl J., Robertson M., Barr E., Haber B.A. Safety and efficacy of elbasvir/grazoprevir in patients with hepatitis C virus infection and compensated cirrhosis: an integrated analysis. Gastroenterology. 2017;152(6):1372–1382. doi: 10.1053/j.gastro.2017.01.050. e1372. PubMed DOI

James J.S. Saquinavir (Invirase): first protease inhibitor approved--reimbursement, information hotline numbers. AIDS Treat. News. 1995;(237):1–2. PubMed

Jeong J.H., Chokkakula S., Min S.C., Kim B.K., Choi W.S., Oh S., Yun Y.S., Kang D.H., Lee O.J., Kim E.G., Choi J.H., Lee J.Y., Choi Y.K., Baek Y.H., Song M.S. Combination therapy with nirmatrelvir and molnupiravir improves the survival of SARS-CoV-2 infected mice. Antivir. Res. 2022;208 doi: 10.1016/j.antiviral.2022.105430. PubMed DOI PMC

Jiang M., Mani N., Lin C., Ardzinski A., Nelson M., Reagan D., Bartels D., Zhou Y., Nicolas O., Rao B.G., Müh U., Hanzelka B., Tigges A., Rijnbrand R., Kieffer T.L. In vitro phenotypic characterization of hepatitis C virus NS3 protease variants observed in clinical studies of telaprevir. Antimicrob. Agents Chemother. 2013;57(12):6236–6245. doi: 10.1128/AAC.01578-13. PubMed DOI PMC

Jin Z., Du X., Xu Y., Deng Y., Liu M., Zhao Y., Zhang B., Li X., Zhang L., Peng C., Duan Y., Yu J., Wang L., Yang K., Liu F., Jiang R., Yang X., You T., Liu X., Yang X., Bai F., Liu H., Liu X., Guddat L.W., Xu W., Xiao G., Qin C., Shi Z., Jiang H., Rao Z., Yang H. Structure of M(pro) from SARS-CoV-2 and discovery of its inhibitors. Nature. 2020;582(7811):289–293. doi: 10.1038/s41586-020-2223-y. PubMed DOI

Jochmans D., Anders M., Keuleers I., Smeulders L., Kräusslich H.-G., Kraus G., Müller B. Selective killing of human immunodeficiency virus infected cells by non-nucleoside reverse transcriptase inhibitor-induced activation of HIV protease. Retrovirology. 2010;7(1):89. doi: 10.1186/1742-4690-7-89. PubMed DOI PMC

Jochmans D., Liu C., Donckers K., Stoycheva A., Boland S., Stevens S.K., De Vita C., Vanmechelen B., Maes P., Trüeb B., Ebert N., Thiel V., De Jonghe S., Vangeel L., Bardiot D., Jekle A., Blatt L.M., Beigelman L., Symons J.A., Raboisson P., Chaltin P., Marchand A., Neyts J., Deval J., Vandyck K. The substitutions L50F, E166A and L167F in SARS-CoV-2 3CLpro are selected by a protease inhibitor in vitro and confer resistance to nirmatrelvir. bioRxiv. 2022 doi: 10.1101/2022.06.07.495116. 2022.2006.2007.495116. PubMed DOI PMC

Kabinger F., Stiller C., Schmitzová J., Dienemann C., Kokic G., Hillen H.S., Höbartner C., Cramer P. Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis. Nat. Struct. Mol. Biol. 2021;28(9):740–746. doi: 10.1038/s41594-021-00651-0. PubMed DOI PMC

Kaldor S.W., Kalish V.J., Davies J.F., Shetty B.V., Fritz J.E., Appelt K., Burgess J.A., Campanale K.M., Chirgadze N.Y., Clawson D.K., Dressman B.A., Hatch S.D., Khalil D.A., Kosa M.B., Lubbehusen P.P., Muesing M.A., Patick A.K., Reich S.H., Su K.S., Tatlock J.H. Viracept (nelfinavir mesylate, AG1343): a potent, orally bioavailable inhibitor of HIV-1 protease. J. Med. Chem. 1997;40(24):3979–3985. doi: 10.1021/jm9704098. PubMed DOI

Kalu N.N., Desai P.J., Shirley C.M., Gibson W., Dennis P.A., Ambinder R.F. Nelfinavir inhibits maturation and export of herpes simplex virus 1. J. Virol. 2014;88(10):5455–5461. doi: 10.1128/JVI.03790-13. PubMed DOI PMC

Kang C., Keller T.H., Luo D. Zika virus protease: an antiviral drug target. Trends Microbiol. 2017;25(10):797–808. doi: 10.1016/j.tim.2017.07.001. PubMed DOI

Kaplan A.H., Swanstrom R. Human immunodeficiency virus type 1 Gag proteins are processed in two cellular compartments. Proc. Natl. Acad. Sci. USA. 1991;88(10):4528–4532. doi: 10.1073/pnas.88.10.4528. PubMed DOI PMC

Kaptein S.J.F., Goethals O., Kiemel D., Marchand A., Kesteleyn B., Bonfanti J.F., Bardiot D., Stoops B., Jonckers T.H.M., Dallmeier K., Geluykens P., Thys K., Crabbe M., Chatel-Chaix L., Münster M., Querat G., Touret F., de Lamballerie X., Raboisson P., Simmen K., Chaltin P., Bartenschlager R., Van Loock M., Neyts J. A pan-serotype dengue virus inhibitor targeting the NS3-NS4B interaction. Nature. 2021;598(7881):504–509. doi: 10.1038/s41586-021-03990-6. PubMed DOI

Kataev V.E., Garifullin B.F. Antiviral nucleoside analogs. Chem. Heterocycl. Compd. 2021;57(4):326–341. doi: 10.1007/s10593-021-02912-8. PubMed DOI PMC

Katsumoto T., Hattori N., Kurimura T. Maturation of human immunodeficiency virus, strain LAV, in vitro. Intervirology. 1987;27(3):148–153. doi: 10.1159/000149733. PubMed DOI

Kausar S., Said Khan F., Ishaq Mujeeb Ur Rehman M., Akram M., Riaz M., Rasool G., Hamid Khan A., Saleem I., Shamim S., Malik A. A review: mechanism of action of antiviral drugs. Int. J. Immunopathol. Pharmacol. 2021;35 doi: 10.1177/20587384211002621. PubMed DOI PMC

Kawabata S., Gills J.J., Mercado-Matos J.R., Lopiccolo J., Wilson W., 3rd, Hollander M.C., Dennis P.A. Synergistic effects of nelfinavir and bortezomib on proteotoxic death of NSCLC and multiple myeloma cells. Cell Death Dis. 2012;3(7):e353. doi: 10.1038/cddis.2012.87. PubMed DOI PMC

Keating G.M. Elbasvir/grazoprevir: first global approval. Drugs. 2016;76(5):617–624. doi: 10.1007/s40265-016-0558-3. PubMed DOI

Kempf D.J., Marsh K.C., Denissen J.F., McDonald E., Vasavanonda S., Flentge C.A., Green B.E., Fino L., Park C.H., Kong X.P. ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans. Proc. Natl. Acad. Sci. U. S. A. 1995;92(7):2484–2488. doi: 10.1073/pnas.92.7.2484. PubMed DOI PMC

Kempf D.J., Marsh K.C., Kumar G., Rodrigues A.D., Denissen J.F., McDonald E., Kukulka M.J., Hsu A., Granneman G.R., Baroldi P.A., Sun E., Pizzuti D., Plattner J.J., Norbeck D.W., Leonard J.M. Pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus protease by coadministration with ritonavir. Antimicrob. Agents Chemother. 1997;41(3):654–660. doi: 10.1128/aac.41.3.654. PubMed DOI PMC

Kempf D.J., Isaacson J.D., King M.S., Brun S.C., Xu Y., Real K., Bernstein B.M., Japour A.J., Sun E., Rode R.A. Identification of genotypic changes in human immunodeficiency virus protease that correlate with reduced susceptibility to the protease inhibitor lopinavir among viral isolates from protease inhibitor-experienced patients. J. Virol. 2001;75(16):7462–7469. doi: 10.1128/jvi.75.16.7462-7469.2001. PubMed DOI PMC

Khayat R., Batra R., Qian C., Halmos T., Bailey M., Tong L. Structural and biochemical studies of inhibitor binding to human cytomegalovirus protease. Biochemistry. 2003;42(4):885–891. doi: 10.1021/bi027045s. PubMed DOI

Kim E., Baker C., Dwyer M., Murcko M., Rao B., Tung R., Navia M. Crystal structure of HIV-1 protease in complex with VX-478, a potent and orally bioavailable inhibitor of the enzyme. J. Am. Chem. Soc. 1995;117(3):1181–1182.

Kim J.L., Morgenstern K.A., Lin C., Fox T., Dwyer M.D., Landro J.A., Chambers S.P., Markland W., Lepre C.A., O'Malley E.T., Harbeson S.L., Rice C.M., Murcko M.A., Caron P.R., Thomson J.A. Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide. Cell. 1996;87(2):343–355. doi: 10.1016/s0092-8674(00)81351-3. PubMed DOI

Klemm T., Ebert G., Calleja D.J., Allison C.C., Richardson L.W., Bernardini J.P., Lu B.G., Kuchel N.W., Grohmann C., Shibata Y., Gan Z.Y., Cooney J.P., Doerflinger M., Au A.E., Blackmore T.R., van der Heden van Noort G.J., Geurink P.P., Ovaa H., Newman J., Riboldi-Tunnicliffe A., Czabotar P.E., Mitchell J.P., Feltham R., Lechtenberg B.C., Lowes K.N., Dewson G., Pellegrini M., Lessene G., Komander D. Mechanism and inhibition of the papain-like protease, PLpro, of SARS-CoV-2. EMBO J. 2020;39(18) doi: 10.15252/embj.2020106275. PubMed DOI PMC

Koh Y., Nakata H., Maeda K., Ogata H., Bilcer G., Devasamudram T., Kincaid J.F., Boross P., Wang Y.F., Tie Y., Volarath P., Gaddis L., Harrison R.W., Weber I.T., Ghosh A.K., Mitsuya H. Novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI) UIC-94017 (TMC114) with potent activity against multi-PI-resistant human immunodeficiency virus in vitro. Antimicrob. Agents Chemother. 2003;47(10):3123–3129. doi: 10.1128/aac.47.10.3123-3129.2003. PubMed DOI PMC

Kohl N.E., Emini E.A., Schleif W.A., Davis L.J., Heimbach J.C., Dixon R.A., Scolnick E.M., Sigal I.S. Active human immunodeficiency virus protease is required for viral infectivity. Proc. Natl. Acad. Sci. U. S. A. 1988;85(13):4686–4690. doi: 10.1073/pnas.85.13.4686. PubMed DOI PMC

Konvalinka J., Litterst M.A., Welker R., Kottler H., Rippmann F., Heuser A.M., Kräusslich H.G. An active-site mutation in the human immunodeficiency virus type 1 proteinase (PR) causes reduced PR activity and loss of PR-mediated cytotoxicity without apparent effect on virus maturation and infectivity. J. Virol. 1995;69(11):7180–7186. doi: 10.1128/jvi.69.11.7180-7186.1995. PubMed DOI PMC

Konvalinka J., Kräusslich H.G., Müller B. Retroviral proteases and their roles in virion maturation. Virology. 2015;479–480:403–417. doi: 10.1016/j.virol.2015.03.021. PubMed DOI

Koster J.C., Remedi M.S., Qiu H., Nichols C.G., Hruz P.W. HIV protease inhibitors acutely impair glucose-stimulated insulin release. Diabetes. 2003;52(7):1695–1700. doi: 10.2337/diabetes.52.7.1695. PubMed DOI PMC

Kožíšek M., Bray J., Řezáčová P., Šašková K., Brynda J., Pokorná J., Mammano F., Rulíšek L., Konvalinka J. Molecular analysis of the HIV-1 resistance development: enzymatic activities, crystal structures, and thermodynamics of nelfinavir-resistant HIV protease mutants. J. Mol. Biol. 2007;374(4):1005–1016. doi: 10.1016/j.jmb.2007.09.083. PubMed DOI

Kozísek M., Henke S., Sasková K.G., Jacobs G.B., Schuch A., Buchholz B., Müller V., Kräusslich H.G., Rezácová P., Konvalinka J., Bodem J. Mutations in HIV-1 gag and pol compensate for the loss of viral fitness caused by a highly mutated protease. Antimicrob. Agents Chemother. 2012;56(8):4320–4330. doi: 10.1128/aac.00465-12. PubMed DOI PMC

Kožíšek M., Lepšík M., Grantz Šašková K., Brynda J., Konvalinka J., Rezáčová P. Thermodynamic and structural analysis of HIV protease resistance to darunavir - analysis of heavily mutated patient-derived HIV-1 proteases. FEBS J. 2014;281(7):1834–1847. doi: 10.1111/febs.12743. PubMed DOI

Kräusslich H.G. Human immunodeficiency virus proteinase dimer as component of the viral polyprotein prevents particle assembly and viral infectivity. Proc. Natl. Acad. Sci. USA. 1991;88(8):3213–3217. doi: 10.1073/pnas.88.8.3213. PubMed DOI PMC

Krishnan P., Tripathi R., Schnell G., Reisch T., Beyer J., Irvin M., Xie W., Larsen L., Cohen D., Podsadecki T., Pilot-Matias T., Collins C. Resistance analysis of baseline and treatment-emergent variants in hepatitis C virus genotype 1 in the AVIATOR study with paritaprevir-ritonavir, ombitasvir, and dasabuvir. Antimicrob. Agents Chemother. 2015;59(9):5445–5454. doi: 10.1128/aac.00998-15. PubMed DOI PMC

Kumar G.N., Rodrigues A.D., Buko A.M., Denissen J.F. Cytochrome P450-mediated metabolism of the HIV-1 protease inhibitor ritonavir (ABT-538) in human liver microsomes. J. Pharmacol. Exp. Therapeut. 1996;277(1):423–431. PubMed

Kuroki A., Tay J., Lee G.H., Yang Y.Y. Broad-spectrum antiviral peptides and polymers. Adv. Healthc. Mater. 2021;10(23) doi: 10.1002/adhm.202101113. PubMed DOI

Kwong A.D., Kim J.L., Rao G., Lipovsek D., Raybuck S.A. Hepatitis C virus NS3/4A protease. Antivir. Res. 1998;40(1–2):1–18. doi: 10.1016/s0166-3542(98)00043-6. PubMed DOI

Kwong A.D., Kauffman R.S., Hurter P., Mueller P. Discovery and development of telaprevir: an NS3-4A protease inhibitor for treating genotype 1 chronic hepatitis C virus. Nat. Biotechnol. 2011;29(11):993–1003. doi: 10.1038/nbt.2020. PubMed DOI

Lamb Y.N. Nirmatrelvir plus ritonavir: first approval. Drugs. 2022;82(5):585–591. doi: 10.1007/s40265-022-01692-5. PubMed DOI PMC

Lander E.S., Linton L.M., Birren B., Nusbaum C., Zody M.C., Baldwin J., Devon K., Dewar K., Doyle M., FitzHugh W., Funke R., Gage D., Harris K., Heaford A., Howland J., Kann L., Lehoczky J., LeVine R., McEwan P., McKernan K., Meldrim J., Mesirov J.P., Miranda C., Morris W., Naylor J., Raymond C., Rosetti M., Santos R., Sheridan A., Sougnez C., Stange-Thomann Y., Stojanovic N., Subramanian A., Wyman D., Rogers J., Sulston J., Ainscough R., Beck S., Bentley D., Burton J., Clee C., Carter N., Coulson A., Deadman R., Deloukas P., Dunham A., Dunham I., Durbin R., French L., Grafham D., Gregory S., Hubbard T., Humphray S., Hunt A., Jones M., Lloyd C., McMurray A., Matthews L., Mercer S., Milne S., Mullikin J.C., Mungall A., Plumb R., Ross M., Shownkeen R., Sims S., Waterston R.H., Wilson R.K., Hillier L.W., McPherson J.D., Marra M.A., Mardis E.R., Fulton L.A., Chinwalla A.T., Pepin K.H., Gish W.R., Chissoe S.L., Wendl M.C., Delehaunty K.D., Miner T.L., Delehaunty A., Kramer J.B., Cook L.L., Fulton R.S., Johnson D.L., Minx P.J., Clifton S.W., Hawkins T., Branscomb E., Predki P., Richardson P., Wenning S., Slezak T., Doggett N., Cheng J.F., Olsen A., Lucas S., Elkin C., Uberbacher E., Frazier M., Gibbs R.A., Muzny D.M., Scherer S.E., Bouck J.B., Sodergren E.J., Worley K.C., Rives C.M., Gorrell J.H., Metzker M.L., Naylor S.L., Kucherlapati R.S., Nelson D.L., Weinstock G.M., Sakaki Y., Fujiyama A., Hattori M., Yada T., Toyoda A., Itoh T., Kawagoe C., Watanabe H., Totoki Y., Taylor T., Weissenbach J., Heilig R., Saurin W., Artiguenave F., Brottier P., Bruls T., Pelletier E., Robert C., Wincker P., Smith D.R., Doucette-Stamm L., Rubenfield M., Weinstock K., Lee H.M., Dubois J., Rosenthal A., Platzer M., Nyakatura G., Taudien S., Rump A., Yang H., Yu J., Wang J., Huang G., Gu J., Hood L., Rowen L., Madan A., Qin S., Davis R.W., Federspiel N.A., Abola A.P., Proctor M.J., Myers R.M., Schmutz J., Dickson M., Grimwood J., Cox D.R., Olson M.V., Kaul R., Raymond C., Shimizu N., Kawasaki K., Minoshima S., Evans G.A., Athanasiou M., Schultz R., Roe B.A., Chen F., Pan H., Ramser J., Lehrach H., Reinhardt R., McCombie W.R., de la Bastide M., Dedhia N., Blöcker H., Hornischer K., Nordsiek G., Agarwala R., Aravind L., Bailey J.A., Bateman A., Batzoglou S., Birney E., Bork P., Brown D.G., Burge C.B., Cerutti L., Chen H.C., Church D., Clamp M., Copley R.R., Doerks T., Eddy S.R., Eichler E.E., Furey T.S., Galagan J., Gilbert J.G., Harmon C., Hayashizaki Y., Haussler D., Hermjakob H., Hokamp K., Jang W., Johnson L.S., Jones T.A., Kasif S., Kaspryzk A., Kennedy S., Kent W.J., Kitts P., Koonin E.V., Korf I., Kulp D., Lancet D., Lowe T.M., McLysaght A., Mikkelsen T., Moran J.V., Mulder N., Pollara V.J., Ponting C.P., Schuler G., Schultz J., Slater G., Smit A.F., Stupka E., Szustakowki J., Thierry-Mieg D., Thierry-Mieg J., Wagner L., Wallis J., Wheeler R., Williams A., Wolf Y.I., Wolfe K.H., Yang S.P., Yeh R.F., Collins F., Guyer M.S., Peterson J., Felsenfeld A., Wetterstrand K.A., Patrinos A., Morgan M.J., de Jong P., Catanese J.J., Osoegawa K., Shizuya H., Choi S., Chen Y.J., Szustakowki J. Initial sequencing and analysis of the human genome. Nature. 2001;409(6822):860–921. doi: 10.1038/35057062. PubMed DOI

Lawitz E., Poordad F., Kowdley K.V., Cohen D.E., Podsadecki T., Siggelkow S., Larsen L., Menon R., Koev G., Tripathi R., Pilot-Matias T., Bernstein B. A phase 2a trial of 12-week interferon-free therapy with two direct-acting antivirals (ABT-450/r, ABT-072) and ribavirin in IL28B C/C patients with chronic hepatitis C genotype 1. J. Hepatol. 2013;59(1):18–23. doi: 10.1016/j.jhep.2013.02.009. PubMed DOI

Lawitz E.J., O'Riordan W.D., Asatryan A., Freilich B.L., Box T.D., Overcash J.S., Lovell S., Ng T.I., Liu W., Campbell A., Lin C.W., Yao B., Kort J. Potent antiviral activities of the direct-acting antivirals ABT-493 and ABT-530 with three-day monotherapy for hepatitis C virus genotype 1 infection. Antimicrob. Agents Chemother. 2015;60(3):1546–1555. doi: 10.1128/aac.02264-15. PubMed DOI PMC

Lawitz E., Reau N., Hinestrosa F., Rabinovitz M., Schiff E., Sheikh A., Younes Z., Herring R., Jr., Reddy K.R., Tran T., Bennett M., Nahass R., Yang J.C., Lu S., Dvory-Sobol H., Stamm L.M., Brainard D.M., McHutchison J.G., Pearlman B., Shiffman M., Hawkins T., Curry M., Jacobson I. Efficacy of sofosbuvir, velpatasvir, and GS-9857 in patients with genotype 1 hepatitis C virus infection in an open-label, phase 2 trial. Gastroenterology. 2016;151(5):893–901. doi: 10.1053/j.gastro.2016.07.039. e891. PubMed DOI

Lawitz E., Poordad F., Wells J., Hyland R.H., Yang Y., Dvory-Sobol H., Stamm L.M., Brainard D.M., McHutchison J.G., Landaverde C., Gutierrez J. Sofosbuvir-velpatasvir-voxilaprevir with or without ribavirin in direct-acting antiviral-experienced patients with genotype 1 hepatitis C virus. Hepatology. 2017;65(6):1803–1809. doi: 10.1002/hep.29130. PubMed DOI

Lebbé C., Blum L., Pellet C., Blanchard G., Vérola O., Morel P., Danne O., Calvo F. Clinical and biological impact of antiretroviral therapy with protease inhibitors on HIV-related Kaposi's sarcoma. AIDS. 1998;12(7):F45–F49. doi: 10.1097/00002030-199807000-00002. PubMed DOI

Lecronier M., Beurton A., Burrel S., Haudebourg L., Deleris R., Le Marec J., Virolle S., Nemlaghi S., Bureau C., Mora P., De Sarcus M., Clovet O., Duceau B., Grisot P.H., Pari M.H., Arzoine J., Clarac U., Boutolleau D., Raux M., Delemazure J., Faure M., Decavele M., Morawiec E., Mayaux J., Demoule A., Dres M. Comparison of hydroxychloroquine, lopinavir/ritonavir, and standard of care in critically ill patients with SARS-CoV-2 pneumonia: an opportunistic retrospective analysis. Crit. Care. 2020;24(1):418. doi: 10.1186/s13054-020-03117-9. PubMed DOI PMC

Lee G.M., Shahian T., Baharuddin A., Gable J.E., Craik C.S. Enzyme inhibition by allosteric capture of an inactive conformation. J. Mol. Biol. 2011;411(5):999–1016. doi: 10.1016/j.jmb.2011.06.032. PubMed DOI PMC

Lee J., Worrall L.J., Vuckovic M., Rosell F.I., Gentile F., Ton A.T., Caveney N.A., Ban F., Cherkasov A., Paetzel M., Strynadka N.C.J. Crystallographic structure of wild-type SARS-CoV-2 main protease acyl-enzyme intermediate with physiological C-terminal autoprocessing site. Nat. Commun. 2020;11(1):5877. doi: 10.1038/s41467-020-19662-4. PubMed DOI PMC

Lei J., Hansen G., Nitsche C., Klein C.D., Zhang L., Hilgenfeld R. Crystal structure of Zika virus NS2B-NS3 protease in complex with a boronate inhibitor. Science. 2016;353(6298):503–505. doi: 10.1126/science.aag2419. PubMed DOI

Lei J., Kusov Y., Hilgenfeld R. Nsp3 of coronaviruses: structures and functions of a large multi-domain protein. Antivir. Res. 2018;149:58–74. doi: 10.1016/j.antiviral.2017.11.001. PubMed DOI PMC

Li H.-C., Yang C.-H., Lo S.-Y. Hepatitis C viral replication complex. Viruses. 2021;13(3):520. doi: 10.3390/v13030520. PubMed DOI PMC

Liang G., Bushman F.D. The human virome: assembly, composition and host interactions. Nat. Rev. Microbiol. 2021;19(8):514–527. doi: 10.1038/s41579-021-00536-5. PubMed DOI PMC

Lin C., Lin K., Luong Y.-P., Rao B.G., Wei Y.-Y., Brennan D.L., Fulghum J.R., Hsiao H.-M., Ma S., Maxwell J.P. In vitro resistance studies of hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061: structural analysis indicates different resistance mechanisms. J. Biol. Chem. 2004;279(17):17508–17514. doi: 10.1074/jbc.M313020200. PubMed DOI

Lin T.I., Lenz O., Fanning G., Verbinnen T., Delouvroy F., Scholliers A., Vermeiren K., Rosenquist A., Edlund M., Samuelsson B., Vrang L., de Kock H., Wigerinck P., Raboisson P., Simmen K. In vitro activity and preclinical profile of TMC435350, a potent hepatitis C virus protease inhibitor. Antimicrob. Agents Chemother. 2009;53(4):1377–1385. doi: 10.1128/aac.01058-08. PubMed DOI PMC

Lin C.W., Dutta S., Asatryan A., Chiu Y.L., Wang H., Clifton J., 2nd, Campbell A., Liu W. Pharmacokinetics, safety, and tolerability of single and multiple doses of ABT-493: a first-in-human study. J. Pharmacol. Sci. 2017;106(2):645–651. doi: 10.1016/j.xphs.2016.10.007. PubMed DOI

Liu C., Shi W., Becker S.T., Schatz D.G., Liu B., Yang Y. Structural basis of mismatch recognition by a SARS-CoV-2 proofreading enzyme. Science. 2021;373(6559):1142–1146. doi: 10.1126/science.abi9310. PubMed DOI PMC

Loharamtaweethong K., Vinyuvat S., Thammasiri J., Chitpakdee S., Supakatitham C., Puripat N. Impact of antiretroviral drugs on PD-L1 expression and copy number gains with clinical outcomes in HIV-positive and -negative locally advanced cervical cancers. Oncol. Lett. 2019;18(6):5747–5758. doi: 10.3892/ol.2019.10963. PubMed DOI PMC

Lohmann V., Koch J.O., Bartenschlager R. Processing pathways of the hepatitis C virus proteins. J. Hepatol. 1996;24(2 Suppl. l):11–19. PubMed

Louis J.M., Aniana A., Weber I.T., Sayer J.M. Inhibition of autoprocessing of natural variants and multidrug resistant mutant precursors of HIV-1 protease by clinical inhibitors. Proc. Natl. Acad. Sci. U. S. A. 2011;108(22):9072–9077. doi: 10.1073/pnas.1102278108. PubMed DOI PMC

Love R.A., Parge H.E., Wickersham J.A., Hostomsky Z., Habuka N., Moomaw E.W., Adachi T., Hostomska Z. The crystal structure of hepatitis C virus NS3 proteinase reveals a trypsin-like fold and a structural zinc binding site. Cell. 1996;87(2):331–342. doi: 10.1016/s0092-8674(00)81350-1. PubMed DOI

Luo D., Vasudevan S.G., Lescar J. The flavivirus NS2B-NS3 protease-helicase as a target for antiviral drug development. Antivir. Res. 2015;118:148–158. doi: 10.1016/j.antiviral.2015.03.014. PubMed DOI

Lv Z., Cano K.E., Jia L., Drag M., Huang T.T., Olsen S.K. Targeting SARS-CoV-2 proteases for COVID-19 antiviral development. Front. Chem. 2022;9 doi: 10.3389/fchem.2021.819165. PubMed DOI PMC

Ma C., Sacco M.D., Hurst B., Townsend J.A., Hu Y., Szeto T., Zhang X., Tarbet B., Marty M.T., Chen Y., Wang J. Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease. Cell Res. 2020;30(8):678–692. doi: 10.1038/s41422-020-0356-z. PubMed DOI PMC

Madison V., Prongay A.J., Guo Z., Yao N., Pichardo J., Fischmann T., Strickland C., Myers J., Jr., Weber P.C., Beyer B.M., Ingram R., Hong Z., Prosise W.W., Ramanathan L., Taremi S.S., Yarosh-Tomaine T., Zhang R., Senior M., Yang R.S., Malcolm B., Arasappan A., Bennett F., Bogen S.L., Chen K., Jao E., Liu Y.T., Lovey R.G., Saksena A.K., Venkatraman S., Girijavallabhan V., Njoroge F.G. Key steps in the structure-based optimization of the hepatitis C virus NS3/4A protease inhibitor SCH5 03034. J. Synchrotron Radiat. 2008;15(Pt 3):204–207. doi: 10.1107/s0909049507064229. PubMed DOI PMC

Majerová T., Konvalinka J. In: Encyclopedia of Biological Chemistry III. third ed. Jez J., editor. Elsevier; Oxford: 2021. Enyzmes | HIV protease; pp. 264–269.

Majerová T., Novotný P. Precursors of viral proteases as distinct drug targets. Viruses. 2021;13(10):1981. PubMed PMC

Majerová T., Hoffman H., Majer F. Therapeutic targets for influenza-Perspectives in drug development. Collect. Czech Chem. Commun. 2010;75(1):81–103. doi: 10.1135/cccc2009087. DOI

Majerová T., Novotný P., Krýsová E., Konvalinka J. Exploiting the unique features of Zika and Dengue proteases for inhibitor design. Biochimie. 2019;166:132–141. doi: 10.1016/j.biochi.2019.05.004. PubMed DOI

Majerová-Uhlíková T., Dantuma N.P., Lindsten K., Masucci M.G., Konvalinka J. Non-infectious fluorimetric assay for phenotyping of drug-resistant HIV proteinase mutants. J. Clin. Virol. 2006;36(1):50–59. doi: 10.1016/j.jcv.2006.01.014. PubMed DOI

Mancuso P., Chen C., Kaminski R., Gordon J., Liao S., Robinson J.A., Smith M.D., Liu H., Sariyer I.K., Sariyer R., Peterson T.A., Donadoni M., Williams J.B., Siddiqui S., Bunnell B.A., Ling B., MacLean A.G., Burdo T.H., Khalili K. CRISPR based editing of SIV proviral DNA in ART treated non-human primates. Nat. Commun. 2020;11(1):6065. doi: 10.1038/s41467-020-19821-7. PubMed DOI PMC

Manns M.P., Buti M., Gane E., Pawlotsky J.-M., Razavi H., Terrault N., Younossi Z. Hepatitis C virus infection. Nat. Rev. Dis. Prim. 2017;3(1) doi: 10.1038/nrdp.2017.6. PubMed DOI

Marcelin A.G., Affolabi D., Lamotte C., Mohand H.A., Delaugerre C., Wirden M., Voujon D., Bossi P., Ktorza N., Bricaire F., Costagliola D., Katlama C., Peytavin G., Calvez V. Resistance profiles observed in virological failures after 24 weeks of amprenavir/ritonavir containing regimen in protease inhibitor experienced patients. J. Med. Virol. 2004;74(1):16–20. doi: 10.1002/jmv.20140. PubMed DOI

Marcellin P., Forns X., Goeser T., Ferenci P., Nevens F., Carosi G., Drenth J.P., Serfaty L., De Backer K., Van Heeswijk R., Luo D., Picchio G., Beumont M. Telaprevir is effective given every 8 or 12 hours with ribavirin and peginterferon alfa-2a or -2b to patients with chronic hepatitis C. Gastroenterology. 2011;140(2):459–468. doi: 10.1053/j.gastro.2010.10.046. e451; quiz e414. PubMed DOI

Markham A., Keam S.J. Danoprevir: first global approval. Drugs. 2018;78(12):1271–1276. doi: 10.1007/s40265-018-0960-0. PubMed DOI

Marks K.M., Jacobson I.M. The first wave: HCV NS3 protease inhibitors telaprevir and boceprevir. Antivir. Ther. 2012;17(6 Pt B):1119–1131. doi: 10.3851/imp2424. PubMed DOI

Marzolini C., Kuritzkes D.R., Marra F., Boyle A., Gibbons S., Flexner C., Pozniak A., Boffito M., Waters L., Burger D., Back D., Khoo S. Prescribing nirmatrelvir-ritonavir: how to recognize and manage drug-drug interactions. Ann. Intern. Med. 2022;175(5):744–746. doi: 10.7326/m22-0281. PubMed DOI PMC

Mathias A.A., German P., Murray B.P., Wei L., Jain A., West S., Warren D., Hui J., Kearney B.P. Pharmacokinetics and pharmacodynamics of GS-9350: a novel pharmacokinetic enhancer without anti-HIV activity. Clin. Pharmacol. Ther. 2010;87(3):322–329. doi: 10.1038/clpt.2009.228. PubMed DOI

Mattei S., Anders M., Konvalinka J., Kräusslich H.G., Briggs J.A., Müller B. Induced maturation of human immunodeficiency virus. J. Virol. 2014;88(23):13722–13731. doi: 10.1128/jvi.02271-14. PubMed DOI PMC

Matthew A.N., Zephyr J., Nageswara Rao D., Henes M., Kamran W., Kosovrasti K., Hedger A.K., Lockbaum G.J., Timm J., Ali A., Kurt Yilmaz N., Schiffer C.A. Avoiding drug resistance by substrate envelope-guided design: toward potent and robust HCV NS3/4A protease inhibitors. mBio. 2020;11(2) doi: 10.1128/mBio.00172-20. PubMed DOI PMC

Matthew A.N., Leidner F., Lockbaum G.J., Henes M., Zephyr J., Hou S., Rao D.N., Timm J., Rusere L.N., Ragland D.A., Paulsen J.L., Prachanronarong K., Soumana D.I., Nalivaika E.A., Kurt Yilmaz N., Ali A., Schiffer C.A. Drug design strategies to avoid resistance in direct-acting antivirals and beyond. Chem. Rev. 2021;121(6):3238–3270. doi: 10.1021/acs.chemrev.0c00648. PubMed DOI PMC

Maxwell E. Treatment of herpes keratitis with 5-iodo-2-deoxyuridine (IDU). A clinical evaluation of 1,500 cases. Am. J. Ophthalmol. 1963;56:571–573. doi: 10.1016/0002-9394(63)90006-0. PubMed DOI

McArthur D.B. Emerging infectious diseases. Nurs. Clin. 2019;54(2):297–311. doi: 10.1016/j.cnur.2019.02.006. PubMed DOI PMC

Meganck R.M., Baric R.S. Developing therapeutic approaches for twenty-first-century emerging infectious viral diseases. Nat. Med. 2021;27(3):401–410. doi: 10.1038/s41591-021-01282-0. PubMed DOI

Mehta R.M., Bansal S., Bysani S., Kalpakam H. A shorter symptom onset to remdesivir treatment (SORT) interval is associated with a lower mortality in moderate-to-severe COVID-19: a real-world analysis. Int. J. Infect. Dis. 2021;106:71–77. doi: 10.1016/j.ijid.2021.02.092. PubMed DOI PMC

Mensa F.J., Lovell S., Pilot-Matias T., Liu W. Glecaprevir/pibrentasvir for the treatment of chronic hepatitis C virus infection. Future Microbiol. 2019;14:89–110. doi: 10.2217/fmb-2018-0233. PubMed DOI

Merolli A., Kasaei L., Ramasamy S., Kolloli A., Kumar R., Subbian S., Feldman L.C. An intra-cytoplasmic route for SARS-CoV-2 transmission unveiled by Helium-ion microscopy. Sci. Rep. 2022;12(1):3794. doi: 10.1038/s41598-022-07867-0. PubMed DOI PMC

Miao M., Jing X., De Clercq E., Li G. Danoprevir for the treatment of hepatitis C virus infection: design, development, and place in therapy. Drug Des. Dev. Ther. 2020;14:2759–2774. doi: 10.2147/dddt.S254754. PubMed DOI PMC

Miller S.L. Amprenavir approved for HIV treatment. Am. J. Health Syst. Pharm. 1999;56(11):1057–1058. doi: 10.1093/ajhp/56.11.1057. PubMed DOI

Mitsuya H., Weinhold K.J., Furman P.A., St Clair M.H., Lehrman S.N., Gallo R.C., Bolognesi D., Barry D.W., Broder S. 3'-Azido-3'-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. Proc. Natl. Acad. Sci. U. S. A. 1985;82(20):7096–7100. doi: 10.1073/pnas.82.20.7096. PubMed DOI PMC

Mody V., Ho J., Wills S., Mawri A., Lawson L., Ebert M., Fortin G.M., Rayalam S., Taval S. Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents. Commun. Biol. 2021;4(1):93. doi: 10.1038/s42003-020-01577-x. PubMed DOI PMC

Morcilla V., Bacchus-Souffan C., Fisher K., Horsburgh B.A., Hiener B., Wang X.Q., Schlub T.E., Fitch M., Hoh R., Hecht F.M., Martin J.N., Deeks S.G., Hellerstein M.K., McCune J.M., Hunt P.W., Palmer S. HIV-1 genomes are enriched in memory CD4(+) T-cells with short half-lives. mBio. 2021;12(5) doi: 10.1128/mBio.02447-21. PubMed DOI PMC

Morello J., Rodriguez-Novoa S., Jimenez-Nacher I., Soriano V. Drug interactions of tipranavir, a new HIV protease inhibitor. Drug Metabol. Lett. 2007;1(1):81–84. doi: 10.2174/187231207779814256. PubMed DOI

Morris A., McCorkindale W., Consortium T.C.M., Drayman N., Chodera J.D., Tay S., London N., Lee A.A. Discovery of SARS-CoV-2 main protease inhibitors using a synthesis-directed de novo design model. Chem. Commun. 2021;57(48):5909–5912. doi: 10.1039/d1cc00050k. PubMed DOI PMC

Murphy R.L., Gulick R.M., DeGruttola V., D'Aquila R.T., Eron J.J., Sommadossi J.P., Currier J.S., Smeaton L., Frank I., Caliendo A.M., Gerber J.G., Tung R., Kuritzkes D.R. Treatment with amprenavir alone or amprenavir with zidovudine and lamivudine in adults with human immunodeficiency virus infection. AIDS Clinical Trials Group 347 Study Team. J. Infect. Dis. 1999;179(4):808–816. doi: 10.1086/314668. PubMed DOI

Nalam M.N.L., Ali A., Altman M.D., Reddy G.S.K.K., Chellappan S., Kairys V., Ozen A., Cao H., Gilson M.K., Tidor B., Rana T.M., Schiffer C.A. Evaluating the substrate-envelope hypothesis: structural analysis of novel HIV-1 protease inhibitors designed to be robust against drug resistance. J. Virol. 2010;84(10):5368–5378. doi: 10.1128/JVI.02531-09. PubMed DOI PMC

Napoli C., Benincasa G., Criscuolo C., Faenza M., Liberato C., Rusciano M. Immune reactivity during COVID-19: implications for treatment. Immunol. Lett. 2021;231:28–34. doi: 10.1016/j.imlet.2021.01.001. PubMed DOI PMC

Nguyen T., McNicholl I., Custodio J.M., Szwarcberg J., Piontkowsky D. Drug interactions with cobicistat- or ritonavir-boosted elvitegravir. AIDS Rev. 2016;18(2):101–111. PubMed

Nie S., Yao Y., Wu F., Wu X., Zhao J., Hua Y., Wu J., Huo T., Lin Y.L., Kneubehl A.R., Vogt M.B., Ferreon J., Rico-Hesse R., Song Y. Synthesis, structure-activity relationships, and antiviral activity of allosteric inhibitors of flavivirus NS2B-NS3 protease. J. Med. Chem. 2021;64(5):2777–2800. doi: 10.1021/acs.jmedchem.0c02070. PubMed DOI PMC

Nijhuis M., van Maarseveen N.M., Lastere S., Schipper P., Coakley E., Glass B., Rovenska M., de Jong D., Chappey C., Goedegebuure I.W., Heilek-Snyder G., Dulude D., Cammack N., Brakier-Gingras L., Konvalinka J., Parkin N., Kräusslich H.G., Brun-Vezinet F., Boucher C.A. A novel substrate-based HIV-1 protease inhibitor drug resistance mechanism. PLoS Med. 2007;4(1):e36. doi: 10.1371/journal.pmed.0040036. PubMed DOI PMC

Nijhuis M., van Maarseveen N.M., Boucher C.A. Antiviral resistance and impact on viral replication capacity: evolution of viruses under antiviral pressure occurs in three phases. Handb. Exp. Pharmacol. 2009;189:299–320. doi: 10.1007/978-3-540-79086-0_11. PubMed DOI

Njoroge F.G., Chen K.X., Shih N.Y., Piwinski J.J. Challenges in modern drug discovery: a case study of boceprevir, an HCV protease inhibitor for the treatment of hepatitis C virus infection. Acc. Chem. Res. 2008;41(1):50–59. doi: 10.1021/ar700109k. PubMed DOI

Oerlemans R., Ruiz-Moreno A.J., Cong Y., Dinesh Kumar N., Velasco-Velazquez M.A., Neochoritis C.G., Smith J., Reggiori F., Groves M.R., Dömling A. Repurposing the HCV NS3–4A protease drug boceprevir as COVID-19 therapeutics. RSC Med. Chem. 2021;12(3):370–379. doi: 10.1039/D0MD00367K. PubMed DOI PMC

Okubo K., Sato A., Isono M., Asano T., Asano T. Nelfinavir induces endoplasmic reticulum stress and sensitizes renal cancer cells to TRAIL. Anticancer Res. 2018;38(8):4505–4514. doi: 10.21873/anticanres.12754. PubMed DOI

Osipiuk J., Azizi S.A., Dvorkin S., Endres M., Jedrzejczak R., Jones K.A., Kang S., Kathayat R.S., Kim Y., Lisnyak V.G., Maki S.L., Nicolaescu V., Taylor C.A., Tesar C., Zhang Y.A., Zhou Z., Randall G., Michalska K., Snyder S.A., Dickinson B.C., Joachimiak A. Structure of papain-like protease from SARS-CoV-2 and its complexes with non-covalent inhibitors. Nat. Commun. 2021;12(1):743. doi: 10.1038/s41467-021-21060-3. PubMed DOI PMC

Owen D.R., Allerton C.M.N., Anderson A.S., Aschenbrenner L., Avery M., Berritt S., Boras B., Cardin R.D., Carlo A., Coffman K.J., Dantonio A., Di L., Eng H., Ferre R., Gajiwala K.S., Gibson S.A., Greasley S.E., Hurst B.L., Kadar E.P., Kalgutkar A.S., Lee J.C., Lee J., Liu W., Mason S.W., Noell S., Novak J.J., Obach R.S., Ogilvie K., Patel N.C., Pettersson M., Rai D.K., Reese M.R., Sammons M.F., Sathish J.G., Singh R.S.P., Steppan C.M., Stewart A.E., Tuttle J.B., Updyke L., Verhoest P.R., Wei L., Yang Q., Zhu Y. An oral SARS-CoV-2 M(pro) inhibitor clinical candidate for the treatment of COVID-19. Science. 2021;374(6575):1586–1593. doi: 10.1126/science.abl4784. PubMed DOI

Pablos I., Machado Y., de Jesus H.C.R., Mohamud Y., Kappelhoff R., Lindskog C., Vlok M., Bell P.A., Butler G.S., Grin P.M., Cao Q.T., Nguyen J.P., Solis N., Abbina S., Rut W., Vederas J.C., Szekely L., Szakos A., Drag M., Kizhakkedathu J.N., Mossman K., Hirota J.A., Jan E., Luo H., Banerjee A., Overall C.M. Mechanistic insights into COVID-19 by global analysis of the SARS-CoV-2 3CL(pro) substrate degradome. Cell Rep. 2021;37(4) doi: 10.1016/j.celrep.2021.109892. PubMed DOI PMC

Palich R., Makinson A., Veyri M., Guihot A., Valantin M.A., Brégigeon-Ronot S., Poizot-Martin I., Solas C., Grabar S., Martin-Blondel G., Spano J.P. Kaposi's sarcoma in virally suppressed people living with HIV: an emerging condition. Cancers. 2021;13(22) doi: 10.3390/cancers13225702. PubMed DOI PMC

Palumbo E. Pegylated interferon and ribavirin treatment for hepatitis C virus infection. Ther. Adv. Chronic. Dis. 2011;2(1):39–45. doi: 10.1177/2040622310384308. PubMed DOI PMC

Pan Y.-Y., Wang S.-M., Huang K.-J., Chiang C.-C., Wang C.-T. Placement of leucine zipper motifs at the carboxyl terminus of HIV-1 protease significantly reduces virion production. PLoS One. 2012;7(3) doi: 10.1371/journal.pone.0032845. PubMed DOI PMC

Pankey G.A., Sabath L.D. Clinical relevance of bacteriostatic versus bactericidal mechanisms of action in the treatment of gram-positive bacterial infections. Clin. Infect. Dis. 2004;38(6):864–870. doi: 10.1086/381972. PubMed DOI

Pardesbio https://www.pardesbio.com/pipeline/

Paredes R., Clotet B. Clinical management of HIV-1 resistance. Antivir. Res. 2010;85(1):245–265. doi: 10.1016/j.antiviral.2009.09.015. PubMed DOI

Park J.H., Sayer J.M., Aniana A., Yu X., Weber I.T., Harrison R.W., Louis J.M. Binding of clinical inhibitors to a model precursor of a rationally selected multidrug resistant HIV-1 protease is significantly weaker than that to the released mature enzyme. Biochemistry. 2016;55(16):2390–2400. doi: 10.1021/acs.biochem.6b00012. PubMed DOI PMC

Park Y.J., Woo H.Y., Heo J., Park S.G., Hong Y.M., Yoon K.T., Kim D.U., Kim G.H., Kim H.H., Song G.A., Cho M. Real-life effectiveness and safety of glecaprevir/pibrentasvir for Korean patients with chronic hepatitis C at a single institution. Gut Liver. 2021;15(3):440–450. doi: 10.5009/gnl19393. PubMed DOI PMC

Patick A.K., Duran M., Cao Y., Shugarts D., Keller M.R., Mazabel E., Knowles M., Chapman S., Kuritzkes D.R., Markowitz M. Genotypic and phenotypic characterization of human immunodeficiency virus type 1 variants isolated from patients treated with the protease inhibitor nelfinavir. Antimicrob. Agents Chemother. 1998;42(10):2637–2644. doi: 10.1128/AAC.42.10.2637. PubMed DOI PMC

Pawar S.D., Freas C., Weber I.T., Harrison R.W. Analysis of drug resistance in HIV protease. BMC bioinform. 2018;19(Suppl. 11):362. doi: 10.1186/s12859-018-2331-y. 362. PubMed DOI PMC

Payne S. Introduction to RNA viruses. Viruses. 2017:97–105. doi: 10.1016/B978-0-12-803109-4.00010-6. PubMed DOI

Perni R.B., Britt S.D., Court J.C., Courtney L.F., Deininger D.D., Farmer L.J., Gates C.A., Harbeson S.L., Kim J.L., Landro J.A., Levin R.B., Luong Y.P., O'Malley E.T., Pitlik J., Rao B.G., Schairer W.C., Thomson J.A., Tung R.D., Van Drie J.H., Wei Y. Inhibitors of hepatitis C virus NS3.4A protease 1. Non-charged tetrapeptide variants. Bioorg. Med. Chem. Lett. 2003;13(22):4059–4063. doi: 10.1016/j.bmcl.2003.08.050. PubMed DOI

Perni R.B., Farmer L.J., Cottrell K.M., Court J.J., Courtney L.F., Deininger D.D., Gates C.A., Harbeson S.L., Kim J.L., Lin C., Lin K., Luong Y.P., Maxwell J.P., Murcko M.A., Pitlik J., Rao B.G., Schairer W.C., Tung R.D., Van Drie J.H., Wilson K., Thomson J.A. Inhibitors of hepatitis C virus NS3.4A protease. Part 3: P2 proline variants. Bioorg. Med. Chem. Lett. 2004;14(8):1939–1942. doi: 10.1016/j.bmcl.2004.01.078. PubMed DOI

Perni R.B., Pitlik J., Britt S.D., Court J.J., Courtney L.F., Deininger D.D., Farmer L.J., Gates C.A., Harbeson S.L., Levin R.B., Lin C., Lin K., Moon Y.C., Luong Y.P., O'Malley E.T., Rao B.G., Thomson J.A., Tung R.D., Van Drie J.H., Wei Y. Inhibitors of hepatitis C virus NS3.4A protease 2. Warhead SAR and optimization. Bioorg. Med. Chem. Lett. 2004;14(6):1441–1446. doi: 10.1016/j.bmcl.2004.01.022. PubMed DOI

Perni R.B., Chandorkar G., Cottrell K.M., Gates C.A., Lin C., Lin K., Luong Y.P., Maxwell J.P., Murcko M.A., Pitlik J., Rao G., Schairer W.C., Van Drie J., Wei Y. Inhibitors of hepatitis C virus NS3.4A protease. Effect of P4 capping groups on inhibitory potency and pharmacokinetics. Bioorg. Med. Chem. Lett. 2007;17(12):3406–3411. doi: 10.1016/j.bmcl.2007.03.090. PubMed DOI

Pettit S.C., Gulnik S., Everitt L., Kaplan A.H. The dimer interfaces of protease and extra-protease domains influence the activation of protease and the specificity of GagPol cleavage. J. Virol. 2003;77(1):366–374. doi: 10.1128/jvi.77.1.366-374.2003. PubMed DOI PMC

Pettit S.C., Everitt L.E., Choudhury S., Dunn B.M., Kaplan A.H. Initial cleavage of the human immunodeficiency virus type 1 GagPol precursor by its activated protease occurs by an intramolecular mechanism. J. Virol. 2004;78(16):8477–8485. doi: 10.1128/jvi.78.16.8477-8485.2004. PubMed DOI PMC

Pettit S.C., Clemente J.C., Jeung J.A., Dunn B.M., Kaplan A.H. Ordered processing of the human immunodeficiency virus type 1 GagPol precursor is influenced by the context of the embedded viral protease. J. Virol. 2005;79(16):10601–10607. doi: 10.1128/jvi.79.16.10601-10607.2005. PubMed DOI PMC

Pia L., Rowland-Jones S. Omicron entry route. Nat. Rev. Immunol. 2022;22(144) doi: 10.1038/s41577-022-00681-9. PubMed DOI PMC

Pierson T.C., Diamond M.S. The continued threat of emerging flaviviruses. Nat. Microbiol. 2020;5(6):796–812. doi: 10.1038/s41564-020-0714-0. PubMed DOI PMC

Piliero P.J. Atazanavir: a novel HIV-1 protease inhibitor. Expet Opin. Invest. Drugs. 2002;11(9):1295–1301. doi: 10.1517/13543784.11.9.1295. PubMed DOI

Pokorná J., Machala L., Rezáčová P., Konvalinka J. Current and novel inhibitors of HIV protease. Viruses. 2009;1(3):1209–1239. doi: 10.3390/v1031209. PubMed DOI PMC

Pol S., Lagaye S. The remarkable history of the hepatitis C virus. Gene Immun. 2019;20(5):436–446. doi: 10.1038/s41435-019-0066-z. PubMed DOI

Preston B.D., Poiesz B.J., Loeb L.A. Fidelity of HIV-1 reverse transcriptase. Science. 1988;242(4882):1168–1171. doi: 10.1126/science.2460924. PubMed DOI

Priya S., Tripathi G., Singh D.B., Jain P., Kumar A. Machine learning approaches and their applications in drug discovery and design. Chem. Biol. Drug Des. 2022;100(1):136–153. doi: 10.1111/cbdd.14057. PubMed DOI

Proia E., Ragno A., Antonini L., Sabatino M., Mladenovič M., Capobianco R., Ragno R. Ligand-based and structure-based studies to develop predictive models for SARS-CoV-2 main protease inhibitors through the 3d-qsar.com portal. J. Comput. Aided Mol. Des. 2022;36(7):483–505. doi: 10.1007/s10822-022-00460-7. PubMed DOI PMC

Prongay A.J., Guo Z., Yao N., Pichardo J., Fischmann T., Strickland C., Myers J., Jr., Weber P.C., Beyer B.M., Ingram R., Hong Z., Prosise W.W., Ramanathan L., Taremi S.S., Yarosh-Tomaine T., Zhang R., Senior M., Yang R.S., Malcolm B., Arasappan A., Bennett F., Bogen S.L., Chen K., Jao E., Liu Y.T., Lovey R.G., Saksena A.K., Venkatraman S., Girijavallabhan V., Njoroge F.G., Madison V. Discovery of the HCV NS3/4A protease inhibitor (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3- [2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (Sch 503034) II. Key steps in structure-based optimization. J. Med. Chem. 2007;50(10):2310–2318. doi: 10.1021/jm060173k. PubMed DOI

Prusoff W.H. Synthesis and biological activities of iododeoxyuridine, an analog of thymidine. Biochim. Biophys. Acta. 1959;32(1):295–296. doi: 10.1016/0006-3002(59)90597-9. PubMed DOI

Qin E., Zhu Q., Yu M., Fan B., Chang G., Si B., Yang B., Peng W., Jiang T., Liu B., Deng Y., Liu H., Zhang Y., Wang C., Li Y., Gan Y., Li X., Lü F., Tan G., Cao W., Yang R., Wang J., Li W., Xu Z., Li Y., Wu Q., Lin W., Chen W., Tang L., Deng Y., Han Y., Li C., Lei M., Li G., Li W., Lü H., Shi J., Tong Z., Zhang F., Li S., Liu B., Liu S., Dong W., Wang J., Wong G.K., Yu J., Yang H. A complete sequence and comparative analysis of a SARS-associated virus (Isolate BJ01) Chin. Sci. Bull. 2003;48(10):941–948. doi: 10.1007/bf03184203. PubMed DOI PMC

Raboisson P., de Kock H., Rosenquist A., Nilsson M., Salvador-Oden L., Lin T.I., Roue N., Ivanov V., Wähling H., Wickström K., Hamelink E., Edlund M., Vrang L., Vendeville S., Van de Vreken W., McGowan D., Tahri A., Hu L., Boutton C., Lenz O., Delouvroy F., Pille G., Surleraux D., Wigerinck P., Samuelsson B., Simmen K. Structure-activity relationship study on a novel series of cyclopentane-containing macrocyclic inhibitors of the hepatitis C virus NS3/4A protease leading to the discovery of TMC435350. Bioorg. Med. Chem. Lett. 2008;18(17):4853–4858. doi: 10.1016/j.bmcl.2008.07.088. PubMed DOI

Ramanathan S., Custodio J.M., Wei X., Wang H., Fordyce M., Dave A., Ling K.H., Szwarcberg J., Kearney B.P. Pharmacokinetics of Co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate after switch from efavirenz/emtricitabine/tenofovir disoproxil fumarate in healthy subjects. J. Acquir. Immune Defic. Syndr. 2016;72(3):281–288. doi: 10.1097/qai.0000000000000959. PubMed DOI

Ratia K., Pegan S., Takayama J., Sleeman K., Coughlin M., Baliji S., Chaudhuri R., Fu W., Prabhakar B.S., Johnson M.E., Baker S.C., Ghosh A.K., Mesecar A.D. A noncovalent class of papain-like protease/deubiquitinase inhibitors blocks SARS virus replication. Proc. Natl. Acad. Sci. U. S. A. 2008;105(42):16119–16124. doi: 10.1073/pnas.0805240105. PubMed DOI PMC

Reesink H.W., Fanning G.C., Farha K.A., Weegink C., Van Vliet A., Van 't Klooster G., Lenz O., Aharchi F., Mariën K., Van Remoortere P., de Kock H., Broeckaert F., Meyvisch P., Van Beirendonck E., Simmen K., Verloes R. Rapid HCV-RNA decline with once daily TMC435: a phase I study in healthy volunteers and hepatitis C patients. Gastroenterology. 2010;138(3):913–921. doi: 10.1053/j.gastro.2009.10.033. PubMed DOI

Ribeiro R.M., Li H., Wang S., Stoddard M.B., Learn G.H., Korber B.T., Bhattacharya T., Guedj J., Parrish E.H., Hahn B.H., Shaw G.M., Perelson A.S. Quantifying the diversification of hepatitis C virus (HCV) during primary infection: estimates of the in vivo mutation rate. PLoS Pathog. 2012;8(8) doi: 10.1371/journal.ppat.1002881. PubMed DOI PMC

Rittweger M., Arastéh K. Clinical pharmacokinetics of darunavir. Clin. Pharmacokinet. 2007;46(9):739–756. doi: 10.2165/00003088-200746090-00002. PubMed DOI

Roberts J.D., Bebenek K., Kunkel T.A. The accuracy of reverse transcriptase from HIV-1. Science. 1988;242(4882):1171–1173. doi: 10.1126/science.2460925. PubMed DOI

Roberts N.A., Martin J.A., Kinchington D., Broadhurst A.V., Craig J.C., Duncan I.B., Galpin S.A., Handa B.K., Kay J., Kröhn A., et al. Rational design of peptide-based HIV proteinase inhibitors. Science. 1990;248(4953):358–361. doi: 10.1126/science.2183354. PubMed DOI

Robins M.J., Robins R.K. The synthesis of 2′,3′-dideoxyadenosine from 2′-deoxyadenosine. J. Am. Chem. Soc. 1964;86(17):3585–3586.

Rodriguez-Torres M., Glass S., Hill J., Freilich B., Hassman D., Di Bisceglie A.M., Taylor J.G., Kirby B.J., Dvory-Sobol H., Yang J.C., An D., Stamm L.M., Brainard D.M., Kim S., Krefetz D., Smith W., Marbury T., Lawitz E. GS-9857 in patients with chronic hepatitis C virus genotype 1-4 infection: a randomized, double-blind, dose-ranging phase 1 study. J. Viral Hepat. 2016;23(8):614–622. doi: 10.1111/jvh.12527. PubMed DOI

Rosenberg S. Recent advances in the molecular biology of hepatitis C virus. J. Mol. Biol. 2001;313(3):451–464. doi: 10.1006/jmbi.2001.5055. PubMed DOI

Rosenquist Å., Samuelsson B., Johansson P.O., Cummings M.D., Lenz O., Raboisson P., Simmen K., Vendeville S., de Kock H., Nilsson M., Horvath A., Kalmeijer R., de la Rosa G., Beumont-Mauviel M. Discovery and development of simeprevir (TMC435), a HCV NS3/4A protease inhibitor. J. Med. Chem. 2014;57(5):1673–1693. doi: 10.1021/jm401507s. PubMed DOI

Rubin R. Baricitinib is first approved COVID-19 immunomodulatory treatment. JAMA. 2022;327(23):2281. doi: 10.1001/jama.2022.9846. 2281. PubMed DOI

Rubin R. From positive to negative to positive again-the mystery of why COVID-19 rebounds in some patients who take Paxlovid. JAMA. 2022;327(24):2380–2382. doi: 10.1001/jama.2022.9925. PubMed DOI

Rut W., Lv Z., Zmudzinski M., Patchett S., Nayak D., Snipas S.J., El Oualid F., Huang T.T., Bekes M., Drag M., Olsen S.K. Activity profiling and crystal structures of inhibitor-bound SARS-CoV-2 papain-like protease: a framework for anti-COVID-19 drug design. Sci. Adv. 2020;6(42) doi: 10.1126/sciadv.abd4596. PubMed DOI PMC

Rut W., Groborz K., Zhang L., Sun X., Zmudzinski M., Pawlik B., Wang X., Jochmans D., Neyts J., Młynarski W., Hilgenfeld R., Drag M. SARS-CoV-2 M(pro) inhibitors and activity-based probes for patient-sample imaging. Nat. Chem. Biol. 2021;17(2):222–228. doi: 10.1038/s41589-020-00689-z. PubMed DOI

Saab S., Gonzalez Y.S., Huber C., Wang A., Juday T. Cost-effectiveness of ombitasvir/paritaprevir/ritonavir, Dasabuvir+Ribavirin for US post-liver transplant recurrent genotype 1 HCV. Liver Int. 2016;36(4):515–521. doi: 10.1111/liv.13033. PubMed DOI

Sadybekov A.A., Sadybekov A.V., Liu Y., Iliopoulos-Tsoutsouvas C., Huang X.P., Pickett J., Houser B., Patel N., Tran N.K., Tong F., Zvonok N., Jain M.K., Savych O., Radchenko D.S., Nikas S.P., Petasis N.A., Moroz Y.S., Roth B.L., Makriyannis A., Katritch V. Synthon-based ligand discovery in virtual libraries of over 11 billion compounds. Nature. 2022;601(7893):452–459. doi: 10.1038/s41586-021-04220-9. PubMed DOI PMC

Santolini E., Pacini L., Fipaldini C., Migliaccio G., Monica N. The NS2 protein of hepatitis C virus is a transmembrane polypeptide. J. Virol. 1995;69(12):7461–7471. doi: 10.1128/jvi.69.12.7461-7471.1995. PubMed DOI PMC

Saribas A.S., Coric P., Bouaziz S., Safak M. Expression of novel proteins by polyomaviruses and recent advances in the structural and functional features of agnoprotein of JC virus, BK virus, and simian virus 40. J. Cell. Physiol. 2019;234(6):8295–8315. doi: 10.1002/jcp.27715. PubMed DOI PMC

Sarrazin C., Hézode C., Zeuzem S., Pawlotsky J.M. Antiviral strategies in hepatitis C virus infection. J. Hepatol. 2012;56(Suppl. 1):S88–S100. doi: 10.1016/s0168-8278(12)60010-5. PubMed DOI

Sasaki M., Tabata K., Kishimoto M., Itakura Y., Kobayashi H., Ariizumi T., Uemura K., Toba S., Kusakabe S., Maruyama Y., Iida S., Nakajima N., Suzuki T., Yoshida S., Nobori H., Sanaki T., Kato T., Shishido T., Hall W.W., Orba Y., Sato A., Sawa H. S-217622, a SARS-CoV-2 main protease inhibitor, decreases viral load and ameliorates COVID-19 severity in hamsters. Sci. Transl. Med. 2022 doi: 10.1126/scitranslmed.abq4064. eabq4064. PubMed DOI PMC

Sasková K.G., Kozísek M., Lepsík M., Brynda J., Rezácová P., Václavíková J., Kagan R.M., Machala L., Konvalinka J. Enzymatic and structural analysis of the I47A mutation contributing to the reduced susceptibility to HIV protease inhibitor lopinavir. Protein Sci. 2008;17(9):1555–1564. doi: 10.1110/ps.036079.108. PubMed DOI PMC

Sasková K.G., Kozísek M., Rezácová P., Brynda J., Yashina T., Kagan R.M., Konvalinka J. Molecular characterization of clinical isolates of human immunodeficiency virus resistant to the protease inhibitor darunavir. J. Virol. 2009;83(17):8810–8818. doi: 10.1128/jvi.00451-09. PubMed DOI PMC

Schneider J., Kent S.B. Enzymatic activity of a synthetic 99 residue protein corresponding to the putative HIV-1 protease. Cell. 1988;54(3):363–368. doi: 10.1016/0092-8674(88)90199-7. PubMed DOI

Schrödinger L., DeLano W. 2020. PyMOL.http://www.pymol.org/pymol Retrieved from.

Seelmeier S., Schmidt H., Turk V., von der Helm K. Human immunodeficiency virus has an aspartic-type protease that can be inhibited by pepstatin A. Proc. Natl. Acad. Sci. U. S. A. 1988;85(18):6612–6616. doi: 10.1073/pnas.85.18.6612. PubMed DOI PMC

Seiwert S.D., Andrews S.W., Jiang Y., Serebryany V., Tan H., Kossen K., Rajagopalan P.T., Misialek S., Stevens S.K., Stoycheva A., Hong J., Lim S.R., Qin X., Rieger R., Condroski K.R., Zhang H., Do M.G., Lemieux C., Hingorani G.P., Hartley D.P., Josey J.A., Pan L., Beigelman L., Blatt L.M. Preclinical characteristics of the hepatitis C virus NS3/4A protease inhibitor ITMN-191 (R7227) Antimicrob. Agents Chemother. 2008;52(12):4432–4441. doi: 10.1128/aac.00699-08. PubMed DOI PMC

Shah D., Freas C., Weber I.T., Harrison R.W. Evolution of drug resistance in HIV protease. BMC Bioinf. 2020;21(Suppl. 18):497. doi: 10.1186/s12859-020-03825-7. PubMed DOI PMC

Sham H.L., Kempf D.J., Molla A., Marsh K.C., Kumar G.N., Chen C.M., Kati W., Stewart K., Lal R., Hsu A., Betebenner D., Korneyeva M., Vasavanonda S., McDonald E., Saldivar A., Wideburg N., Chen X., Niu P., Park C., Jayanti V., Grabowski B., Granneman G.R., Sun E., Japour A.J., Leonard J.M., Plattner J.J., Norbeck D.W. ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease. Antimicrob. Agents Chemother. 1998;42(12):3218–3224. doi: 10.1128/aac.42.12.3218. PubMed DOI PMC

Shaqra A.M., Zvornicanin S.N., Huang Q.Y.J., Lockbaum G.J., Knapp M., Tandeske L., Bakan D.T., Flynn J., Bolon D.N.A., Moquin S., Dovala D., Kurt Yilmaz N., Schiffer C.A. Defining the substrate envelope of SARS-CoV-2 main protease to predict and avoid drug resistance. Nat. Commun. 2022;13(1):3556. doi: 10.1038/s41467-022-31210-w. PubMed DOI PMC

Sharp P.M., Hahn B.H. Origins of HIV and the AIDS pandemic. Cold Spring Harb. Perspect. Med. 2011;1(1):a006841. doi: 10.1101/cshperspect.a006841. PubMed DOI PMC

Sheahan T.P., Sims A.C., Graham R.L., Menachery V.D., Gralinski L.E., Case J.B., Leist S.R., Pyrc K., Feng J.Y., Trantcheva I., Bannister R., Park Y., Babusis D., Clarke M.O., Mackman R.L., Spahn J.E., Palmiotti C.A., Siegel D., Ray A.S., Cihlar T., Jordan R., Denison M.R., Baric R.S. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci. Transl. Med. 2017;9(396) doi: 10.1126/scitranslmed.aal3653. PubMed DOI PMC

Shehu-Xhilaga M., Crowe S.M., Mak J. Maintenance of the gag/gag-pol ratio is important for human immunodeficiency virus type 1 RNA dimerization and viral infectivity. J. Virol. 2001;75(4):1834–1841. doi: 10.1128/JVI.75.4.1834-1841.2001. PubMed DOI PMC

Sheik Amamuddy O., Afriyie Boateng R., Barozi V., Wavinya Nyamai D., Tastan Bishop Ö. Novel dynamic residue network analysis approaches to study allosteric modulation: SARS-CoV-2 Mpro and its evolutionary mutations as a case study. Comput. Struct. Biotechnol. J. 2021;19:6431–6455. doi: 10.1016/j.csbj.2021.11.016. PubMed DOI PMC

Shekhar C., Nasam R., Paipuri S.R., Kumar P., Nayani K., Pabbaraja S., Mainkar P.S., Chandrasekhar S. Total synthesis of antiviral drug, nirmatrelvir (PF-07321332) Tetrahedron Chem. 2022;4 doi: 10.1016/j.tchem.2022.100033. PubMed DOI PMC

Shepherd S.J., Abdelrahman T., MacLean A.R., Thomson E.C., Aitken C., Gunson R.N. Prevalence of HCV NS3 pre-treatment resistance associated amino acid variants within a Scottish cohort. J. Clin. Virol. 2015;65:50–53. doi: 10.1016/j.jcv.2015.02.005. PubMed DOI PMC

Sherman E.M., Worley M.V., Unger N.R., Gauthier T.P., Schafer J.J. Cobicistat: review of a pharmacokinetic enhancer for HIV infection. Clin. Therapeut. 2015;37(9):1876–1893. doi: 10.1016/j.clinthera.2015.07.022. PubMed DOI

Shetty B.V., Kosa M.B., Khalil D.A., Webber S. Preclinical pharmacokinetics and distribution to tissue of AG1343, an inhibitor of human immunodeficiency virus type 1 protease. Antimicrob. Agents Chemother. 1996;40(1):110–114. doi: 10.1128/aac.40.1.110. PubMed DOI PMC

Shimba N., Nomura A.M., Marnett A.B., Craik C.S. Herpesvirus protease inhibition by dimer disruption. J. Virol. 2004;78(12):6657–6665. doi: 10.1128/jvi.78.12.6657-6665.2004. PubMed DOI PMC

Shin D., Mukherjee R., Grewe D., Bojkova D., Baek K., Bhattacharya A., Schulz L., Widera M., Mehdipour A.R., Tascher G., Geurink P.P., Wilhelm A., van der Heden van Noort G.J., Ovaa H., Müller S., Knobeloch K.-P., Rajalingam K., Schulman B.A., Cinatl J., Hummer G., Ciesek S., Dikic I. Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity. Nature. 2020;587(7835):657–662. doi: 10.1038/s41586-020-2601-5. PubMed DOI PMC

Shuai H., Chan J.F., Hu B., Chai Y., Yuen T.T., Yin F., Huang X., Yoon C., Hu J.C., Liu H., Shi J., Liu Y., Zhu T., Zhang J., Hou Y., Wang Y., Lu L., Cai J.P., Zhang A.J., Zhou J., Yuan S., Brindley M.A., Zhang B.Z., Huang J.D., To K.K., Yuen K.Y., Chu H. Attenuated replication and pathogenicity of SARS-CoV-2 B.1.1.529 Omicron. Nature. 2022;603(7902):693–699. doi: 10.1038/s41586-022-04442-5. PubMed DOI

Siegel R.D. 2018. Classification of Human Viruses. Principles and Practice of Pediatric Infectious Diseases. 1044-1048. DOI

Simmonds P., Aiewsakun P., Katzourakis A. Prisoners of war - host adaptation and its constraints on virus evolution. Nat. Rev. Microbiol. 2019;17(5):321–328. doi: 10.1038/s41579-018-0120-2. PubMed DOI PMC

Singh T.U., Parida S., Lingaraju M.C., Kesavan M., Kumar D., Singh R.K. Drug repurposing approach to fight COVID-19. Pharmacol. Rep. 2020;72(6):1479–1508. doi: 10.1007/s43440-020-00155-6. PubMed DOI PMC

Skwarecki A.S., Nowak M.G., Milewska M.J. Amino acid and peptide-based antiviral agents. ChemMedChem. 2021;16(20):3106–3135. doi: 10.1002/cmdc.202100397. PubMed DOI

Smart T. FDA triple header. Food and Drug Administration. GMHC Treat. Iss. 1995;9(11):1–3. PubMed

Smith D.B., Bukh J., Kuiken C., Muerhoff A.S., Rice C.M., Stapleton J.T., Simmonds P. Expanded classification of hepatitis C virus into 7 genotypes and 67 subtypes: updated criteria and genotype assignment web resource. Hepatology. 2014;59(1):318–327. doi: 10.1002/hep.26744. PubMed DOI PMC

Sorbo M.C., Cento V., Di Maio V.C., Howe A.Y.M., Garcia F., Perno C.F., Ceccherini-Silberstein F. Hepatitis C virus drug resistance associated substitutions and their clinical relevance: update 2018. Drug Resist. Updates. 2018;37:17–39. doi: 10.1016/j.drup.2018.01.004. PubMed DOI

Spira S., Wainberg M.A., Loemba H., Turner D., Brenner B.G. Impact of clade diversity on HIV-1 virulence, antiretroviral drug sensitivity and drug resistance. J. Antimicrob. Chemother. 2003;51(2):229–240. doi: 10.1093/jac/dkg079. PubMed DOI

Steinkühler C., Biasiol G., Brunetti M., Urbani A., Koch U., Cortese R., Pessi A., De Francesco R. Product inhibition of the hepatitis C virus NS3 protease. Biochemistry. 1998;37(25):8899–8905. doi: 10.1021/bi980313v. PubMed DOI

Subeha M.R., Telleria C.M. The anti-cancer properties of the HIV protease inhibitor nelfinavir. Cancers. 2020;12(11) doi: 10.3390/cancers12113437. PubMed DOI PMC

Sudo S., Haraguchi H., Hirai Y., Gatanaga H., Sakuragi J.-i., Momose F., Morikawa Y. Efavirenz enhances HIV-1 gag processing at the plasma membrane through gag-pol dimerization. J. Virol. 2013;87(6):3348–3360. doi: 10.1128/JVI.02306-12. PubMed DOI PMC

Summa V., Ludmerer S.W., McCauley J.A., Fandozzi C., Burlein C., Claudio G., Coleman P.J., Dimuzio J.M., Ferrara M., Di Filippo M., Gates A.T., Graham D.J., Harper S., Hazuda D.J., Huang Q., McHale C., Monteagudo E., Pucci V., Rowley M., Rudd M.T., Soriano A., Stahlhut M.W., Vacca J.P., Olsen D.B., Liverton N.J., Carroll S.S. MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants. Antimicrob. Agents Chemother. 2012;56(8):4161–4167. doi: 10.1128/aac.00324-12. PubMed DOI PMC

Sun L., Niu L., Zhu X., Hao J., Wang P., Wang H. Antitumour effects of a protease inhibitor, nelfinavir, in hepatocellular carcinoma cancer cells. J. Chemother. 2012;24(3):161–166. doi: 10.1179/1973947812y.0000000011. PubMed DOI

Sutton S.S., Magagnoli J., Cummings T., Hardin J. Association between the use of antibiotics, antivirals, and hospitalizations among patients with laboratory-confirmed influenza. Clin. Infect. Dis. 2021;72(4):566–573. doi: 10.1093/cid/ciaa074. PubMed DOI

Svicher V., Ceccherini-Silberstein F., Erba F., Santoro M., Gori C., Bellocchi M.C., Giannella S., Trotta M.P., Monforte A., Antinori A., Perno C.F. Novel human immunodeficiency virus type 1 protease mutations potentially involved in resistance to protease inhibitors. Antimicrob. Agents Chemother. 2005;49(5):2015–2025. doi: 10.1128/aac.49.5.2015-2025.2005. PubMed DOI PMC

Tabler C.O., Wegman S.J., Chen J., Shroff H., Alhusaini N., Tilton J.C. The HIV-1 viral protease is activated during assembly and budding prior to particle release. J. Virol. 2022;96(9) doi: 10.1128/jvi.02198-21. PubMed DOI PMC

Tanramluk D., Pakotiprapha D., Phoochaijaroen S., Chantravisut P., Thampradid S., Vanichtanankul J., Narupiyakul L., Akavipat R., Yuvaniyama J. MANORAA: a machine learning platform to guide protein-ligand design by anchors and influential distances. Structure. 2022;30(1):181–189. doi: 10.1016/j.str.2021.09.004. e185. PubMed DOI

Taylor J.G., Zipfel S., Ramey K., Vivian R., Schrier A., Karki K.K., Katana A., Kato D., Kobayashi T., Martinez R., Sangi M., Siegel D., Tran C.V., Yang Z.-Y., Zablocki J., Yang C.Y., Wang Y., Wang K., Chan K., Barauskas O., Cheng G., Jin D., Schultz B.E., Appleby T., Villaseñor A.G., Link J.O. Discovery of the pan-genotypic hepatitis C virus NS3/4A protease inhibitor voxilaprevir (GS-9857): a component of Vosevi. Bioorg. Med. Chem. Lett. 2019;29(16):2428–2436. doi: 10.1016/j.bmcl.2019.03.037. PubMed DOI

Thaisrivongs S., Strohbach J.W. Structure-based discovery of Tipranavir disodium (PNU-140690E): a potent, orally bioavailable, nonpeptidic HIV protease inhibitor. Biopolymers. 1999;51(1):51–58. doi: 10.1002/(sici)1097-0282(1999)51:1<51::Aid-bip6>3.0.Co;2-u. PubMed DOI

Thaisrivongs S., Skulnick H.I., Turner S.R., Strohbach J.W., Tommasi R.A., Johnson P.D., Aristoff P.A., Judge T.M., Gammill R.B., Morris J.K., Romines K.R., Chrusciel R.A., Hinshaw R.R., Chong K.-T., Tarpley W.G., Poppe S.M., Slade D.E., Lynn J.C., Horng M.-M., Tomich P.K., Seest E.P., Dolak L.A., Howe W.J., Howard G.M., Schwende F.J., Toth L.N., Padbury G.E., Wilson G.J., Shiou L., Zipp G.L., Wilkinson K.F., Rush B.D., Ruwart M.J., Koeplinger K.A., Zhao Z., Cole S., Zaya R.M., Kakuk T.J., Janakiraman M.N., Watenpaugh K.D. Structure-based design of HIV protease inhibitors: sulfonamide-containing 5,6-Dihydro-4-hydroxy-2-pyrones as non-peptidic inhibitors. J. Med. Chem. 1996;39(22):4349–4353. doi: 10.1021/jm960541s. PubMed DOI

Thompson W.J., Ghosh A.K., Holloway M.K., Lee H.Y., Munson P.M., Schwering J.E., Wai J., Darke P.L., Zugay J., Emini E.A., Schleif W.A., Huff J.R., Anderson P.S. 3'-Tetrahydrofuranylglycine as a novel, unnatural amino acid surrogate for asparagine in the design of inhibitors of the HIV protease. J. Am. Chem. Soc. 1993;115(2):801–803. doi: 10.1021/ja00055a069. PubMed DOI PMC

Todosmedical https://todosmedical.com/tollovir

Tomei L., Failla C., Vitale R.L., Bianchi E., De Francesco R. A central hydrophobic domain of the hepatitis C virus NS4A protein is necessary and sufficient for the activation of the NS3 protease. J. Gen. Virol. 1996;77(Pt 5):1065–1070. doi: 10.1099/0022-1317-77-5-1065. PubMed DOI

Tong L., Qian C., Massariol M.J., Bonneau P.R., Cordingley M.G., Lagacé L. A new serine-protease fold revealed by the crystal structure of human cytomegalovirus protease. Nature. 1996;383(6597):272–275. doi: 10.1038/383272a0. PubMed DOI

Tong L., Qian C., Massariol M.J., Déziel R., Yoakim C., Lagacé L. Conserved mode of peptidomimetic inhibition and substrate recognition of human cytomegalovirus protease. Nat. Struct. Biol. 1998;5(9):819–826. doi: 10.1038/1860. PubMed DOI

Tong X., Chase R., Skelton A., Chen T., Wright-Minogue J., Malcolm B.A. Identification and analysis of fitness of resistance mutations against the HCV protease inhibitor SCH 503034. Antivir. Res. 2006;70(2):28–38. doi: 10.1016/j.antiviral.2005.12.003. PubMed DOI

Tong X., Arasappan A., Bennett F., Chase R., Feld B., Guo Z., Hart A., Madison V., Malcolm B., Pichardo J., Prongay A., Ralston R., Skelton A., Xia E., Zhang R., Njoroge F.G. Preclinical characterization of the antiviral activity of SCH 900518 (narlaprevir), a novel mechanism-based inhibitor of hepatitis C virus NS3 protease. Antimicrob. Agents Chemother. 2010;54(6):2365–2370. doi: 10.1128/aac.00135-10. PubMed DOI PMC

Toots M., Yoon J.J., Cox R.M., Hart M., Sticher Z.M., Makhsous N., Plesker R., Barrena A.H., Reddy P.G., Mitchell D.G., Shean R.C., Bluemling G.R., Kolykhalov A.A., Greninger A.L., Natchus M.G., Painter G.R., Plemper R.K. Characterization of orally efficacious influenza drug with high resistance barrier in ferrets and human airway epithelia. Sci. Transl. Med. 2019;11(515) doi: 10.1126/scitranslmed.aax5866. PubMed DOI PMC

Toots M., Yoon J.J., Hart M., Natchus M.G., Painter G.R., Plemper R.K. Quantitative efficacy paradigms of the influenza clinical drug candidate EIDD-2801 in the ferret model. Transl. Res. 2020;218:16–28. doi: 10.1016/j.trsl.2019.12.002. PubMed DOI PMC

Traynor K. Two drugs approved for chronic hepatitis C infection. Am. J. Health Syst. Pharm. 2011;68(13):1176. doi: 10.2146/news110042. PubMed DOI

Tremblay C.L. Combating HIV resistance - focus on darunavir. Therapeut. Clin. Risk Manag. 2008;4(4):759–766. doi: 10.2147/tcrm.s1709. PubMed DOI PMC

Trinité B., Zhang H., Levy D.N. NNRTI-induced HIV-1 protease-mediated cytotoxicity induces rapid death of CD4 T cells during productive infection and latency reversal. Retrovirology. 2019;16(1):17. doi: 10.1186/s12977-019-0479-9. PubMed DOI PMC

Trovato M., Sartorius R., D'Apice L., Manco R., De Berardinis P. Viral emerging diseases: challenges in developing vaccination strategies. Front. Immunol. 2020;11:2130. doi: 10.3389/fimmu.2020.02130. PubMed DOI PMC

Tseng A., Seet J., Phillips E.J. The evolution of three decades of antiretroviral therapy: challenges, triumphs and the promise of the future. Br. J. Clin. Pharmacol. 2015;79(2):182–194. doi: 10.1111/bcp.12403. PubMed DOI PMC

Tsu B.V., Fay E.J., Nguyen K.T., Corley M.R., Hosuru B., Dominguez V.A., Daugherty M.D. Running with scissors: evolutionary conflicts between viral proteases and the host immune system. Front. Immunol. 2021;12 doi: 10.3389/fimmu.2021.769543. PubMed DOI PMC

Unoh Y., Uehara S., Nakahara K., Nobori H., Yamatsu Y., Yamamoto S., Maruyama Y., Taoda Y., Kasamatsu K., Suto T., Kouki K., Nakahashi A., Kawashima S., Sanaki T., Toba S., Uemura K., Mizutare T., Ando S., Sasaki M., Orba Y., Sawa H., Sato A., Sato T., Kato T., Tachibana Y. Discovery of S-217622, a noncovalent oral SARS-CoV-2 3CL protease inhibitor clinical candidate for treating COVID-19. J. Med. Chem. 2022;65(9):6499–6512. doi: 10.1021/acs.jmedchem.2c00117. PubMed DOI PMC

Utkina-Sosunova I.V., Niatsetskaya Z.V., Sosunov S.A., Ratner V.I., Matsiukevich D., Ten V.S. Nelfinavir inhibits intra-mitochondrial calcium influx and protects brain against hypoxic-ischemic injury in neonatal mice. PLoS One. 2013;8(4) doi: 10.1371/journal.pone.0062448. PubMed DOI PMC

V'Kovski P., Kratzel A., Steiner S., Stalder H., Thiel V. Coronavirus biology and replication: implications for SARS-CoV-2. Nat. Rev. Microbiol. 2021;19(3):155–170. doi: 10.1038/s41579-020-00468-6. PubMed DOI PMC

Vacca J.P., Guare J.P., deSolms S.J., Sanders W.M., Giuliani E.A., Young S.D., Darke P.L., Zugay J., Sigal I.S., Schleif W.A., et al. L-687,908, a potent hydroxyethylene-containing HIV protease inhibitor. J. Med. Chem. 1991;34(3):1225–1228. doi: 10.1021/jm00107a050. PubMed DOI

Vacca J.P., Dorsey B.D., Schleif W.A., Levin R.B., McDaniel S.L., Darke P.L., Zugay J., Quintero J.C., Blahy O.M., Roth E., et al. L-735,524: an orally bioavailable human immunodeficiency virus type 1 protease inhibitor. Proc. Natl. Acad. Sci. U. S. A. 1994;91(9):4096–4100. doi: 10.1073/pnas.91.9.4096. PubMed DOI PMC

van Boheemen S., de Graaf M., Lauber C., Bestebroer T.M., Raj V.S., Zaki A.M., Osterhaus A.D., Haagmans B.L., Gorbalenya A.E., Snijder E.J., Fouchier R.A. Genomic characterization of a newly discovered coronavirus associated with acute respiratory distress syndrome in humans. mBio. 2012;3(6) doi: 10.1128/mBio.00473-12. PubMed DOI PMC

van Heeswijk R.P., Veldkamp A., Mulder J.W., Meenhorst P.L., Lange J.M., Beijnen J.H., Hoetelmans R.M. Combination of protease inhibitors for the treatment of HIV-1-infected patients: a review of pharmacokinetics and clinical experience. Antivir. Ther. 2001;6(4):201–229. PubMed

Vangeel L., Chiu W., De Jonghe S., Maes P., Slechten B., Raymenants J., André E., Leyssen P., Neyts J., Jochmans D. Remdesivir, Molnupiravir and Nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern. Antivir. Res. 2022;198 doi: 10.1016/j.antiviral.2022.105252. PubMed DOI PMC

Venkatraman S. Discovery of boceprevir, a direct-acting NS3/4A protease inhibitor for treatment of chronic hepatitis C infections. Trends Pharmacol. Sci. 2012;33(5):289–294. doi: 10.1016/j.tips.2012.03.012. PubMed DOI

Venkatraman S., Bogen S.L., Arasappan A., Bennett F., Chen K., Jao E., Liu Y.T., Lovey R., Hendrata S., Huang Y., Pan W., Parekh T., Pinto P., Popov V., Pike R., Ruan S., Santhanam B., Vibulbhan B., Wu W., Yang W., Kong J., Liang X., Wong J., Liu R., Butkiewicz N., Chase R., Hart A., Agrawal S., Ingravallo P., Pichardo J., Kong R., Baroudy B., Malcolm B., Guo Z., Prongay A., Madison V., Broske L., Cui X., Cheng K.C., Hsieh Y., Brisson J.M., Prelusky D., Korfmacher W., White R., Bogdanowich-Knipp S., Pavlovsky A., Bradley P., Saksena A.K., Ganguly A., Piwinski J., Girijavallabhan V., Njoroge F.G. Discovery of (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]- 3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (SCH 503034), a selective, potent, orally bioavailable hepatitis C virus NS3 protease inhibitor: a potential therapeutic agent for the treatment of hepatitis C infection. J. Med. Chem. 2006;49(20):6074–6086. doi: 10.1021/jm060325b. PubMed DOI

Vitoria M., Rangaraj A., Ford N., Doherty M. Current and future priorities for the development of optimal HIV drugs. Curr. Opin. HIV AIDS. 2019;14(2) PubMed

Vogel M., Rockstroh J.K. Safety of lopinavir/ritonavir for the treatment of HIV-infection. Expet Opin. Drug Saf. 2005;4(3):403–420. doi: 10.1517/14740338.4.3.403. PubMed DOI

von Hentig N. Atazanavir/ritonavir: a review of its use in HIV therapy. Drugs Today. 2008;44(2):103–132. doi: 10.1358/dot.2008.44.2.1137107. PubMed DOI

Wang Q., Gao H., Clark K.M., Mugisha C.S., Davis K., Tang J.P., Harlan G.H., DeSelm C.J., Presti R.M., Kutluay S.B., Shan L. CARD8 is an inflammasome sensor for HIV-1 protease activity. Science. 2021;371(6535) doi: 10.1126/science.abe1707. PubMed DOI PMC

Ward A.R., Mota T.M., Jones R.B. Immunological approaches to HIV cure. Semin. Immunol. 2021;51 doi: 10.1016/j.smim.2020.101412. PubMed DOI

Warren T.K., Jordan R., Lo M.K., Ray A.S., Mackman R.L., Soloveva V., Siegel D., Perron M., Bannister R., Hui H.C., Larson N., Strickley R., Wells J., Stuthman K.S., Van Tongeren S.A., Garza N.L., Donnelly G., Shurtleff A.C., Retterer C.J., Gharaibeh D., Zamani R., Kenny T., Eaton B.P., Grimes E., Welch L.S., Gomba L., Wilhelmsen C.L., Nichols D.K., Nuss J.E., Nagle E.R., Kugelman J.R., Palacios G., Doerffler E., Neville S., Carra E., Clarke M.O., Zhang L., Lew W., Ross B., Wang Q., Chun K., Wolfe L., Babusis D., Park Y., Stray K.M., Trancheva I., Feng J.Y., Barauskas O., Xu Y., Wong P., Braun M.R., Flint M., McMullan L.K., Chen S.-S., Fearns R., Swaminathan S., Mayers D.L., Spiropoulou C.F., Lee W.A., Nichol S.T., Cihlar T., Bavari S. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature. 2016;531(7594):381–385. doi: 10.1038/nature17180. PubMed DOI PMC

Weber J., Mesters J.R., Lepsík M., Prejdová J., Svec M., Sponarová J., Mlcochová P., Skalická K., Strísovský K., Uhlíková T., Soucek M., Machala L., Stanková M., Vondrásek J., Klimkait T., Kraeusslich H.G., Hilgenfeld R., Konvalinka J. Unusual binding mode of an HIV-1 protease inhibitor explains its potency against multi-drug-resistant virus strains. J. Mol. Biol. 2002;324(4):739–754. doi: 10.1016/s0022-2836(02)01139-7. PubMed DOI

Weber I.T., Kneller D.W., Wong-Sam A. Highly resistant HIV-1 proteases and strategies for their inhibition. Future Med. Chem. 2015;7(8):1023–1038. doi: 10.4155/fmc.15.44. PubMed DOI PMC

Weichseldorfer M., Reitz M., Latinovic O.S. Past HIV-1 medications and the current status of combined antiretroviral therapy options for HIV-1 patients. Pharmaceutics. 2021;13(11):1798. doi: 10.3390/pharmaceutics13111798. PubMed DOI PMC

Weikl T.R., Hemmateenejad B. Accessory mutations balance the marginal stability of the HIV-1 protease in drug resistance. Proteins. 2020;88(3):476–484. doi: 10.1002/prot.25826. PubMed DOI

Wen W., Chen C., Tang J., Wang C., Zhou M., Cheng Y., Zhou X., Wu Q., Zhang X., Feng Z., Wang M., Mao Q. Efficacy and safety of three new oral antiviral treatment (molnupiravir, fluvoxamine and Paxlovid) for COVID-19：a meta-analysis. Ann. Med. 2022;54(1):516–523. doi: 10.1080/07853890.2022.2034936. PubMed DOI PMC

Wensing A.M., van Maarseveen N.M., Nijhuis M. Fifteen years of HIV Protease Inhibitors: raising the barrier to resistance. Antivir. Res. 2010;85(1):59–74. doi: 10.1016/j.antiviral.2009.10.003. PubMed DOI

WHO https://www.who.int/news-room/fact-sheets/detail/hepatitis-c

Williamson B.N., Feldmann F., Schwarz B., Meade-White K., Porter D.P., Schulz J., van Doremalen N., Leighton I., Yinda C.K., Pérez-Pérez L., Okumura A., Lovaglio J., Hanley P.W., Saturday G., Bosio C.M., Anzick S., Barbian K., Cihlar T., Martens C., Scott D.P., Munster V.J., de Wit E. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. Nature. 2020;585(7824):273–276. doi: 10.1038/s41586-020-2423-5. PubMed DOI PMC

Wire M.B., Shelton M.J., Studenberg S. Fosamprenavir : clinical pharmacokinetics and drug interactions of the amprenavir prodrug. Clin. Pharmacokinet. 2006;45(2):137–168. doi: 10.2165/00003088-200645020-00002. PubMed DOI

Wutzler P., Thust R. Genetic risks of antiviral nucleoside analogues--a survey. Antivir. Res. 2001;49(2):55–74. doi: 10.1016/s0166-3542(00)00139-x. PubMed DOI

Xia C., He Z., Liang S., Chen R., Xu W., Yang J., Xiao G., Jiang S. Metformin combined with nelfinavir induces SIRT3/mROS-dependent autophagy in human cervical cancer cells and xenograft in nude mice. Eur. J. Pharmacol. 2019;848:62–69. doi: 10.1016/j.ejphar.2019.01.045. PubMed DOI

Yang K.S., Leeuwon S.Z., Xu S., Liu W.R. Evolutionary and structural insights about potential SARS-CoV-2 evasion of nirmatrelvir. J. Med. Chem. 2022 doi: 10.1021/acs.jmedchem.2c00404. PubMed DOI PMC

You D.M., Pockros P.J. Simeprevir for the treatment of chronic hepatitis C. Expet Opin. Pharmacother. 2013;14(18):2581–2589. doi: 10.1517/14656566.2013.850074. PubMed DOI

Yousefi H., Mashouri L., Okpechi S.C., Alahari N., Alahari S.K. Repurposing existing drugs for the treatment of COVID-19/SARS-CoV-2 infection: a review describing drug mechanisms of action. Biochem. Pharmacol. 2021;183 doi: 10.1016/j.bcp.2020.114296. PubMed DOI PMC

Zehbe I., Richard C., Lee K.F., Campbell M., Hampson L., Hampson I.N. Lopinavir shows greater specificity than zinc finger ejecting compounds as a potential treatment for human papillomavirus-related lesions. Antivir. Res. 2011;91(2):161–166. doi: 10.1016/j.antiviral.2011.05.016. PubMed DOI

Zephyr J., Kurt Yilmaz N., Schiffer C.A. Viral proteases: structure, mechanism and inhibition. Enzymes. 2021;50:301–333. doi: 10.1016/bs.enz.2021.09.004. PubMed DOI PMC

Zephyr J., Nageswara Rao D., Vo S.V., Henes M., Kosovrasti K., Matthew A.N., Hedger A.K., Timm J., Chan E.T., Ali A., Kurt Yilmaz N., Schiffer C.A. Deciphering the molecular mechanism of HCV protease inhibitor fluorination as a general approach to avoid drug resistance. J. Mol. Biol. 2022;434(9) doi: 10.1016/j.jmb.2022.167503. PubMed DOI PMC

Zeuzem S., Ghalib R., Reddy K.R., Pockros P.J., Ben Ari Z., Zhao Y., Brown D.D., Wan S., DiNubile M.J., Nguyen B.Y., Robertson M.N., Wahl J., Barr E., Butterton J.R. Grazoprevir-elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic hepatitis C virus genotype 1, 4, or 6 infection: a randomized trial. Ann. Intern. Med. 2015;163(1):1–13. doi: 10.7326/m15-0785. PubMed DOI

Zhang Y., Lee A.A. Bayesian semi-supervised learning for uncertainty-calibrated prediction of molecular properties and active learning. Chem. Sci. 2019;10(35):8154–8163. doi: 10.1039/c9sc00616h. PubMed DOI PMC

Zhang Y.M., Imamichi H., Imamichi T., Lane H.C., Falloon J., Vasudevachari M.B., Salzman N.P. Drug resistance during indinavir therapy is caused by mutations in the protease gene and in its Gag substrate cleavage sites. J. Virol. 1997;71(9):6662–6670. doi: 10.1128/jvi.71.9.6662-6670.1997. PubMed DOI PMC

Zhang L., Lin D., Sun X., Curth U., Drosten C., Sauerhering L., Becker S., Rox K., Hilgenfeld R. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science. 2020;368(6489):409–412. doi: 10.1126/science.abb3405. PubMed DOI PMC

Zhang T.-h., Dai L., Barton J.P., Du Y., Tan Y., Pang W., Chakraborty A.K., Lloyd-Smith J.O., Sun R. Predominance of positive epistasis among drug resistance-associated mutations in HIV-1 protease. PLoS Genet. 2020;16(10) doi: 10.1371/journal.pgen.1009009. PubMed DOI PMC

Zhang X., Shang L., Fan G., Gu X., Xu J., Wang Y., Huang L., Cao B. The efficacy and safety of Janus kinase inhibitors for patients with COVID-19: a living systematic review and meta-analysis. Front. Med. 2021;8 doi: 10.3389/fmed.2021.800492. PubMed DOI PMC

Zhang Y., Luo M., Wu P., Wu S., Lee T.Y., Bai C. Application of computational biology and artificial intelligence in drug design. Int. J. Mol. Sci. 2022;23(21) doi: 10.3390/ijms232113568. PubMed DOI PMC

Zhao Y., Fang C., Zhang Q., Zhang R., Zhao X., Duan Y., Wang H., Zhu Y., Feng L., Zhao J., Shao M., Yang X., Zhang L., Peng C., Yang K., Ma D., Rao Z., Yang H. 2021. Crystal Structure of SARS-CoV-2 Main Protease in Complex with Protease Inhibitor PF-07321332. Protein & Cell. PubMed DOI PMC

Zhou S., Hill C.S., Sarkar S., Tse L.V., Woodburn B.M.D., Schinazi R.F., Sheahan T.P., Baric R.S., Heise M.T., Swanstrom R. β-d-N4-hydroxycytidine inhibits SARS-CoV-2 through lethal mutagenesis but is also mutagenic to mammalian cells. J. Infect. Dis. 2021;224(3):415–419. doi: 10.1093/infdis/jiab247. PubMed DOI PMC

Zhou Y., Gammeltoft K.A., Ryberg L.A., Pham L.V., Fahnøe U., Binderup A., Hernandez C.R.D., Offersgaard A., Fernandez-Antunez C., Peters G.H.J., Ramirez S., Bukh J., Gottwein J.M. bioRxiv; 2022. Nirmatrelvir Resistant SARS-CoV-2 Variants with High Fitness in Vitro. 2022.2006.2006.494921. PubMed DOI PMC

The zymogenic form of SARS-CoV-2 main protease: A discrete target for drug discovery