Compounds with a phosphonate group, i.e., -P(O)(OH)2 group attached directly to the molecule via a P-C bond serve as suitable non-hydrolyzable phosphate mimics in various biomedical applications. In principle, they often inhibit enzymes utilizing various phosphates as substrates. In this review we focus mainly on biologically active phosphonates that originated from our institute (Institute of Organic Chemistry and Biochemistry in Prague); i.e., acyclic nucleoside phosphonates (ANPs, e.g., adefovir, tenofovir, and cidofovir) and derivatives of non-nucleoside phosphonates such as 2-(phosphonomethyl) pentanedioic acid (2-PMPA). Principal strategies of their syntheses and modifications to prodrugs is reported. Besides clinically used ANP antivirals, a special attention is paid to new biologically active molecules with respect to emerging infections and arising resistance of many pathogens against standard treatments. These new structures include 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]pyrimidines or so-called "open-ring" derivatives, acyclic nucleoside phosphonates with 5-azacytosine as a base moiety, side-chain fluorinated ANPs, aza/deazapurine ANPs. When transformed into an appropriate prodrug by derivatizing their charged functionalities, all these compounds show promising potential to become drug candidates for the treatment of viral infections. ANP prodrugs with suitable pharmacokinetics include amino acid phosphoramidates, pivaloyloxymethyl (POM) and isopropoxycarbonyloxymethyl (POC) esters, alkyl and alkoxyalkyl esters, salicylic esters, (methyl-2-oxo-1,3-dioxol-4-yl) methyl (ODOL) esters and peptidomimetic prodrugs. We also focus on the story of cytostatics related to 9-[2-(phosphonomethoxy)ethyl]guanine and its prodrugs which eventually led to development of the veterinary drug rabacfosadine. Various new ANP structures are also currently investigated as antiparasitics, especially antimalarial agents e.g., guanine and hypoxanthine derivatives with 2-(phosphonoethoxy)ethyl moiety, their thia-analogues and N-branched derivatives. In addition to ANPs and their analogs, we also describe prodrugs of 2-(phosphonomethyl)pentanedioic acid (2-PMPA), a potent inhibitor of the enzyme glutamate carboxypeptidase II (GCPII), also known as prostate-specific membrane antigen (PSMA). Glutamate carboxypeptidase II inhibitors, including 2-PMPA have been found efficacious in various preclinical models of neurological disorders which are caused by glutamatergic excitotoxicity. Unfortunately its highly polar character and hence low bioavailability severely limits its potential for clinical use. To overcome this problem, various prodrug strategies have been used to mask carboxylates and/or phosphonate functionalities with pivaloyloxymethyl, POC, ODOL and alkyl esters. Chemistry and biological characterization led to identification of prodrugs with 44-80 fold greater oral bioavailability (tetra-ODOL-2-PMPA).

Departments of Neurology Pharmacology and Molecular Sciences Johns Hopkins Drug Discovery Baltimore MD United States

Departments of Neurology Pharmacology and Molecular Sciences Psychiatry and Behavioral Sciences Neuroscience Medicine Oncology Johns Hopkins Drug Discovery Baltimore MD United States

Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic Prague Czechia

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Alcamo A. M., Wolf M. S., Alessi L. J., Chong H. J., Green M., Williams J. V. (2020). Successful Use of Cidofovir in an Immunocompetent Child with Severe Adenoviral Sepsis. Pediatrics 145 (1), 1632. 10.1542/peds.2019-1632 PubMed DOI PMC

Andrei G., Snoeck R. (2010). Cidofovir Activity against Poxvirus Infections. Viruses-Basel 2 (12), 2803–2830. 10.3390/v2122803 PubMed DOI PMC

Andrei G., Topalis D., De Schutter T., Snoeck R. (2015). Insights into the Mechanism of Action of Cidofovir and Other Acyclic Nucleoside Phosphonates against Polyoma- and Papillomaviruses and Non-viral Induced Neoplasia. Antivir. Res. 114, 21–46. 10.1016/j.antiviral.2014.10.012 PubMed DOI

Arimilli M. N., Dougherty J., Cundy K. C., Bischofberger N. (1999). Orally Bioavailable Acyclic Nucleoside Phosphonate Prodrugs: Adefovir Dipivoxil and bis(POC)PMPA. Adv. Antivir. Drug Res. 3, 69–91. 10.1016/s1075-8593(99)80004-5 DOI

Arimilli M. N., Kim C. U., Dougherty J., Mulato A., Oliyai R., Shaw J. P., et al. (1997). Synthesis, In Vitro Biological Evaluation and Oral Bioabailability of 9-[2-(phosphonomethoxy)propyl]adenine (PMPA) Prodrugs. Antivir. Chem. Chemother. 8 (6), 557–564. 10.1177/095632029700800610 DOI

Babu K. S., Reddy M. S., Tagore A. R., Reddy G. S., Sebastian S., Varma M. S., et al. (2009). Efficient Synthesis of Olmesartan Medoxomil, an Antihypertensive Drug. Synth. Commun. 39 (2), 291–298. 10.1080/00397910802372558 DOI

Balzarini J., Aquaro S., Perno C.-F., Witvrouw M., Holý A., De Clercq E. (1996). Activity of the (R)-enantiomers of 9-(2-phosphonylmethoxypropyl) Adenine and 9-(2-Phosphonylmethoxypropyl)-2,6-Diaminopurine against Human Immunodeficiency Virus in Different Human Cell Systems. Biochem. Biophys. Res. Commun. 219 (2), 337–341. 10.1006/bbrc.1996.0234 PubMed DOI

Balzarini J., Holý A., Jindřich J., Dvořáková H., Hao Z., Snoeck R., et al. (1991). 9-[(2RS)-3-fluoro-2-phosphonylmethoxypropyl] Derivatives of Purines: a Class of Highly Selective Antiretroviral Agents In Vitro and In Vivo . Proc. Natl. Acad. Sci. U. S. A. 88 (11), 4961–4965. 10.1073/pnas.88.11.4961 PubMed DOI PMC

Balzarini J., Holý A., Jindrich J., Naesens L., Snoeck R., Schols D., et al. (1993). Differential Antiherpesvirus and Antiretrovirus Effects of the (S) and (R) Enantiomers of Acyclic Nucleoside Phosphonates: Potent and Selective In Vitro and In Vivo Antiretrovirus Activities of (R)-9-(2-phosphonomethoxypropyl)-2,6-diaminopurine. Antimicrob. Agents Chemother. 37 (2), 332–338. 10.1128/AAC.37.2.332 PubMed DOI PMC

Balzarini J., Pannecouque C., De Clercq E., Aquaro S., Perno C. F., Egberink H., et al. (2002). Antiretrovirus Activity of a Novel Class of Acyclic Pyrimidine Nucleoside Phosphonates. Antimicrob. Agents Chemother. 46 (7), 2185–2193. 10.1128/AAC.46.7.2185-2193.2002 PubMed DOI PMC

Bařinka C., Mlčochová P., Šácha P., Hilgert I., Majer P., Slusher B. S., et al. (2004). Amino Acids at the N- and C-Termini of Human Glutamate Carboxypeptidase II Are Required for Enzymatic Activity and Proper Folding. Eur. J. Biochem. 271 (13), 2782–2790. 10.1111/j.1432-1033.2004.04209.x PubMed DOI

Bařinka C., Rojas C., Slusher B. S., Pomper M. (2012). Glutamate Carboxypeptidase II in Diagnosis and Treatment of Neurologic Disorders and Prostate Cancer. Curr. Med. Chem. 19 (6), 856–870. 10.2174/092986712799034888 PubMed DOI PMC

Baszczyňski O., Janeba Z. (2013). Medicinal Chemistry of Fluorinated Cyclic and Acyclic Nucleoside Phosphonates. Med. Res. Rev. 33 (6), 1304–1344. 10.1002/med.21296 PubMed DOI

Beadle J. R., Hartline C., Aldern K. A., Rodriguez N., Harden E., Kern E. R., et al. (2002). Alkoxyalkyl Esters of Cidofovir and Cyclic Cidofovir Exhibit Multiple-Log Enhancement of Antiviral Activity against Cytomegalovirus and Herpesvirus Replication In Vitro . Antimicrob. Agents Chemother. 46 (8), 2381–2386. 10.1128/AAC.46.8.2381-2386.2002 PubMed DOI PMC

Benzaria S., Pelicano H., Johnson R., Maury G., Imbach J. L., Aubertin A. M., et al. (1996). Synthesis, In Vitro Antiviral Evaluation, and Stability Studies of bis(S-Acyl-2-Thioethyl) Ester Derivatives of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) as Potential PMEA Prodrugs with Improved Oral Bioavailability. J. Med. Chem. 39 (25), 4958–4965. 10.1021/jm960289o PubMed DOI

Birkus G., Bam R. A., Willkom M., Frey C. R., Tsai L., Stray K. M., et al. (2016). Intracellular Activation of Tenofovir Alafenamide and the Effect of Viral and Host Protease Inhibitors. Antimicrob. Agents Chemother. 60 (1), 316–322. 10.1128/AAC.01834-15 PubMed DOI PMC

Břehová P., Chaloupecká E., Česnek M., Skácel J., Dračínský M., Tloušťová E., et al. (2021). Acyclic Nucleoside Phosphonates with 2-aminothiazole Base as Inhibitors of Bacterial and Mammalian Adenylate Cyclases. Eur. J. Med. Chem. 222, 113581. 10.1016/j.ejmech.2021.113581 PubMed DOI PMC

Břehová P., Šmídková M., Skácel J., Dračínský M., Mertlíková-Kaiserová H., Velasquez M. P. S., et al. (2016). Design and Synthesis of Fluorescent Acyclic Nucleoside Phosphonates as Potent Inhibitors of Bacterial Adenylate Cyclases. ChemMedChem 11 (22), 2534–2546. 10.1002/cmdc.201600439 PubMed DOI PMC

Brousil J. A., Burke J. M. J. C. (2003). Olmesartan Medoxomil: an Angiotensin II-Receptor Blocker. Clin. Ther. 25 (4), 1041–1055. 10.1016/S0149-2918(03)80066-8 PubMed DOI

Cahard D., McGuigan C., Balzarini J. (2004). Aryloxy Phosphoramidate Triesters as Pro-tides. Mini Rev. Med. Chem. 4 (4), 371–378. 10.2174/1389557043403936 PubMed DOI

Česnek M., Jansa P., Šmídková M., Mertlíková-Kaiserová H., Dračínský M., Brust T. F., et al. (2015). Bisamidate Prodrugs of 2-substituted 9- 2-(phosphonomethoxy)ethyl Adenine (PMEA, Adefovir) as Selective Inhibitors of Adenylate Cyclase Toxin from Bordetella Pertussis. ChemMedChem 10 (8), 1351–1364. 10.1002/cmdc.201500183 PubMed DOI

Česnek M., Šafránek M., Dračínský M., Tloušťová E., Mertlíková-Kaiserová H., Hayes M. P., et al. (2022). Halogen-Dance-Based Synthesis of Phosphonomethoxyethyl (PME) Substituted 2-Aminothiazoles as Potent Inhibitors of Bacterial Adenylate Cyclases. ChemMedChem 17 (1), e202100568. 10.1002/cmdc.202100568 PubMed DOI PMC

Česnek M., Skácel J., Jansa P., Dračínský M., Šmídková M., Mertlíková-Kaiserová H., et al. (2018). Nucleobase Modified Adefovir (PMEA) Analogues as Potent and Selective Inhibitors of Adenylate Cyclases from Bordetella Pertussis and Bacillus Anthracis. ChemMedChem 13 (17), 1779–1796. 10.1002/cmdc.201800332 PubMed DOI PMC

Chapman H., Kernan M., Prisbe E., Rohloff J., Sparacino M., Terhorst T., et al. (2001). Practical Synthesis, Separation, and Stereochemical Assignment of the PMPA Pro-drug GS-7340. Nucleosides, Nucleotides, Nucleic Acids 20 (4-7), 621–628. 10.1081/NCN-100002338 PubMed DOI

Chatalic K. L. S., Heskamp S., Konijnenberg M., Molkenboer-Kuenen J. D. M., Franssen G. M., Clahsen-van Groningen M. C., et al. (2016). Towards Personalized Treatment of Prostate Cancer: PSMA I&T, a Promising Prostate-specific Membrane Antigen-Targeted Theranostic Agent. Theranostics 6 (6), 849–861. 10.7150/thno.14744 PubMed DOI PMC

Chen W., Flavin M. T., Filler R., Xu Z. Q. (1996). An Improved Synthesis of 9-[2-(diethoxyphosphonomethoxy)ethyl]adenine and its Analogues with Other Purine Bases Utilizing the Mitsunobu Reaction. Nucleosides Nucleotides 15 (11-12), 1771–1778. 10.1080/07328319608002731 DOI

Cheng X., Cook G. P., Desai M. (2005). Phosphonates, Monophosphonamidates Bisphosphonamidates for the Treatment of Viral Diseases. U.S. Patent No WO2005066189 A1. Foster City, CA, United States: Gilead Sciences, Inc. Publication date 21. 07. 2005.

Cihlar T., Birkus G., Greenwalt D. E., Hitchcock M. J. M. (2002). Tenofovir Exhibits Low Cytotoxicity in Various Human Cell Types: Comparison with Other Nucleoside Reverse Transcriptase Inhibitors. Antivir. Res. 54 (1), 37–45. 10.1016/S0166-3542(01)00210-8 PubMed DOI

Clinical.trials.gov (2021). Brincidofovir. Available at: https://clinicaltrials.gov/ct2/results?term=brincidofovir&Search=Search .

Clinical.trials.gov (2014). GS-9219. Available at: http://clinicaltrials.gov/ct2/results?term=GS-9219&Search=Search .

Compton M. L., Toole J. J., Paborsky L. R. (1999). 9-(2-Phosphonylmethoxyethyl)-N-6- Cyclopropyl-2,6-Diaminopurine (Cpr-PMEDAP) as a Prodrug of 9-(2- Phosphonylmethoxyethyl)guanine (PMEG). Biochem. Pharmacol. 58 (4), 709–714. 10.1016/S0006-2952(99)00138-0 PubMed DOI

Cundy K. C. (1999). Clinical Pharmacokinetics of the Antiviral Nucleotide Analogues Cidofovir and Adefovir. Clin. Pharmacokinet. 36 (2), 127–143. 10.2165/00003088-199936020-00004 PubMed DOI

Dash R. P., Tichý T., Veeravalli V., Lam J., Alt J., Wu Y., et al. (2019). Enhanced Oral Bioavailability of 2-(Phosphonomethyl)-Pentanedioic Acid (2-PMPA) from its (5-Methyl-2-Oxo-1,3-Dioxol-4-Yl)methyl (ODOL)-Based Prodrugs. Mol. Pharm. 16 (10), 4292–4301. 10.1021/acs.molpharmaceut.9b00637 PubMed DOI PMC

Date A. A., Rais R., Babu T., Ortiz J., Kanvinde P., Thomas A. G., et al. (2017). Local Enema Treatment to Inhibit FOLH1/GCPII as a Novel Therapy for Inflammatory Bowel Disease. J. Control Release 263, 132–138. 10.1016/j.jconrel.2017.01.036 PubMed DOI PMC

De Clercq E. (2007). Acyclic Nucleoside Phosphonates: Past, Present and Future. Bridging Chemistry to HIV, HBV, HCV, HPV, Adeno-, Herpes-, and Poxvirus Infections: The Phosphonate Bridge. Biochem. Pharmacol. 73 (7), 911–922. 10.1016/j.bcp.2006.09.014 PubMed DOI

De Clercq E., Andrei G., Balzarini J., Leyssen P., Naesens L., Neyts J., et al. (2005). Antiviral Potential of a New Generation of Acyclic Nucleoside Phosphonates, the 6-[2-(phosphonomethoxy)alkoxy]-2,4-Diaminopyrimidines. Nucleosides, Nucleotides Nucleic Acids 24 (5-7SI), 331–341. 10.1081/NCN-200059772 PubMed DOI

De Clercq E. (2009). Antiviral Drug Discovery: Ten More Compounds, and Ten More Stories (Part B). Med. Res. Rev. 29 (4), 571–610. 10.1002/med.20149 PubMed DOI

De Clercq E. (2019). Fifty Years in Search of Selective Antiviral Drugs. J. Med. Chem. 62 (16), 7322–7339. 10.1021/acs.jmedchem.9b00175 PubMed DOI

De Clercq E., Holý A. (2005). Acyclic Nucleoside Phosphonates: A Key Class of Antiviral Drugs. Nat. Rev. Drug Discov. 4 (11), 928–940. 10.1038/nrd1877 PubMed DOI

De Clercq E. (2018). Tanovea® for the Treatment of Lymphoma in Dogs. Biochem. Pharmacol. 154, 265–269. 10.1016/j.bcp.2018.05.010 PubMed DOI

De Clercq E. (2016). Tenofovir Alafenamide (TAF) as the Successor of Tenofovir Disoproxil Fumarate (TDF). Biochem. Pharmacol. 119, 1–7. 10.1016/j.bcp.2016.04.015 PubMed DOI

De Clercq E. (2013). The Acyclic Nucleoside Phosphonates (ANPs): Antonín Holy’s Legacy. Med. Res. Rev. 33 (6SI), 1278–1303. 10.1002/med.21283 PubMed DOI

De Clercq E. (2011). The Clinical Potential of the Acyclic (And Cyclic) Nucleoside Phosphonates. The Magic of the Phosphonate Bond. Biochem. Pharmacol. 82 (2), 99–109. 10.1016/j.bcp.2011.03.027 PubMed DOI

de Fraga R. S., Van Vaisberg V., Mendes L. C. A., Carrilho F. J., Ono S. K. (2020). Adverse Events of Nucleos(t)ide Analogues for Chronic Hepatitis B: a Systematic Review. J. Gastroenterol. 55 (5), 496–514. 10.1007/s00535-020-01680-0 PubMed DOI PMC

De Jersey J., Holý A., Hocková D., Naesens L., Keough D. T., Guddat L. W. (2011). 6-Oxopurine Phosphoribosyltransferase: A Target for the Development of Antimalarial Drugs. Curr. Top. Med. Chem. 11 (16), 2085–2102. 10.2174/156802611796575911 PubMed DOI

Deeks E. D., Perry C. M. (2010). Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate Single-Tablet Regimen (Atripla (R)). A Review of its Use in the Management of HIV Infection. Drugs 70 (17), 2315–2338. 10.2165/11203800-000000000-00000 PubMed DOI

Doležalová E., Klejch T., Špaček P., Slapničková M., Guddat L., Hocková D., et al. (2021). Acyclic Nucleoside Phosphonates with Adenine Nucleobase Inhibit Trypanosoma Brucei Adenine Phosphoribosyltransferase In Vitro . Sci. Rep. 11, 13317. 10.1038/s41598-021-91747-6 PubMed DOI PMC

Doleželová E., Terán D., Gahura O., Kotrbová Z., Procházková M., Keough D., et al. (2018). Evaluation of the Trypanosoma Brucei 6-oxopurine Salvage Pathway as a Potential Target for Drug Discovery. PLoS Negl. Trop. Dis. 12 (2), e0006301. 10.1371/journal.pntd.0006301 PubMed DOI PMC

Dračínský M., Krečmerová M., Holý A. (2008). Study of Chemical Stability of Antivirally Active -5azacytosine Acyclic Nucleoside Phosphonates Using NMR Spectroscopy. Bioorg. Med. Chem. 16 (14), 6778–6782. 10.1016/j.bmc.2008.05.058 PubMed DOI

Drugs.com (2021). Cidofovir. Available at: https://www.drugs.com/monograph/cidofovir.html (Accessed June 9, 2021).

Dunning J., Kennedy S: B., Antierens A., Whitehead J., Ciglenecki I., Carson G., et al. (2016). Experimental Treatment of Ebola Virus Disease with Brincidofovir. Plos One 11 (9), e0162199. 10.1371/journal.pone.0162199 PubMed DOI PMC

Elanco (2021). Tanovea®(rabacfosadine for injection). Available at: https://www.elanco.us/products-services/dogs/tanovea.

Eriksson U., Peterson L. W., Kashemirov B. A., Hilfinger J. M., Drach J. C., Borysko K. Z., et al. (2008). Serine Peptide Phosphoester Prodrugs of Cyclic Cidofovir: Synthesis, Transport and Antiviral Activity. Mol. Pharm. 5 (4), 598–609. 10.1021/mp8000099 PubMed DOI PMC

Erion M. D., Reddy K. R., Boyer S. H., Matelich M. C., Gornez-Galeno J., Lemus R. H., et al. (2004). Design, Synthesis, and Characterization of a Series of Cytochrome P-450 3A-Activated Prodrugs (HepDirect Prodrugs) Useful for Targeting Phosph(on)ate-Based Drugs to the Liver. J. Am. Chem. Soc. 126 (16), 5154–5163. 10.1021/ja031818y PubMed DOI

Esteban-Gamboa A., Balzarini J., Esnouf R., De Clercq E., Camarasa M. J., Perez-Perez M. J. (2000). Design, Synthesis, and Enzymatic Evaluation of Multisubstrate Analogue Inhibitors of Escherichia coli Thymidine Phosphorylase. J. Med. Chem. 43 (5), 971–983. 10.1021/jm9911377 PubMed DOI

F. D. A. (2021). FDA . Available at: https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-drug-treat-smallpox (Accessed June 4, 2021).

Feng J. F., Van K. C., Gurkoff G. G., Kopriva C., Olszewski R. T., Song M., et al. (2011). Post-injury Administration of NAAG Peptidase Inhibitor Prodrug, PGI-02776, in Experimental TBI. Brain Res. 1395, 62–73. 10.1016/j.brainres.2011.04.022 PubMed DOI PMC

Ferraris D. V., Shukla K., Tsukamoto T. (2012). Structure-activity Relationships of Glutamate Carboxypeptidase II (GCPII) Inhibitors. Curr. Med. Chem. 19 (9), 1282–1294. 10.2174/092986712799462658 PubMed DOI

Folkman J., Shing Y. (1992). Angiogenesis. J. Biol. Chem. 267 (16), 10931–10934. 10.1016/s0021-9258(19)49853-0 PubMed DOI

Fontaine H., Vallet-Pichard A., Chaix M.-L., Currie G., Serpaggi J., Verkarre V., et al. (2005). Efficacy and Safety of Adefovir Dipivoxil in Kidney Recipients, Hemodialysis Patients, and Patients with Renal Insufficiency. Transplantation 80 (8), 1086–1092. 10.1097/01.tp.0000178305.39231.a2 PubMed DOI

Foss C. A., Mease R. C., Fan H., Wang Y., Ravert H. T., Dannals R. F., et al. (2005). Radiolabeled Small-Molecule Ligands for Prostate-specific Membrane Antigen: In Vivo Imaging in Experimental Models of Prostate Cancer. Clin. Cancer Res. 11 (11), 4022–4028. 10.1158/1078-0432.CCR-04-2690 PubMed DOI

Friedmann P. S., Lee M. S., Friedmann A. C., Barnetson R. S. C. (2003). Mechanisms in Cutaneous Drug Hypersensitivity Reactions. Clin. Exp. Allergy 33 (7), 861–872. 10.1046/j.1365-2222.2003.01718.x PubMed DOI

Gao Y., Zheng H., Li L., Feng M., Chen X., Hao B., et al. (2021). Prostate-Specific Membrane Antigen (PSMA) Promotes Angiogenesis of Glioblastoma through Interacting with ITGB4 and Regulating NF-Κb Signaling Pathway. Front. Cell Dev. Biol. 9, 598377. 10.3389/fcell.2021.598377 PubMed DOI PMC

Garaga S., Misra N. C., Raghava Reddy A. V., Prabahar K. J., Takshinamoorthy C., Sanasi P. D., et al. (2015). Commercial Synthesis of Azilsartan Kamedoxomil: An Angiotensin II Receptor Blocker. Org. Process Res. Dev. 19 (4), 514–519. 10.1021/op500357r DOI

Ghadge G. D., Slusher B. S., Bodner A., Canto M. D., Wozniak K., Thomas A., et al. (2003). Glutamate Carboxypeptidase II Inhibition Protects Motor Neurons from Death in Familial Amyotrophic Lateral Sclerosis Models. Proc. Natl. Acad. Sci. U. S. A. 100 (16), 9554–9559. 10.1073/pnas.1530168100 PubMed DOI PMC

Gi R. E. A. T. P., Dietz A., Djukic V., Eckel H. E., Friedrich G., Golusinski W., et al. (2012). Treatment of Recurrent Respiratory Papillomatosis and Adverse Reactions Following Off-Label Use of Cidofovir (Vistide®). Eur. Arch. Otorhinolaryngol. 269 (2), 361–362. 10.1007/s00405-011-1804-7 PubMed DOI PMC

Gibb D. M., Kizito H., Russell E. C., Chidziva E., Zalwango E., Nalumenya R., et al. (2012). Pregnancy and Infant Outcomes Among HIV-Infected Women Taking Long-Term ART with and without Tenofovir in the DART Trial. Plos Med. 9 (5), e1001217. 10.1371/journal.pmed.1001217 PubMed DOI PMC

Gil-Fernandez C., Garcia-Villalon D., De Clercq E., Rosenberg I., Holý A. (1987). Phosphonylmethoxyalkylpurines and –pyrimidines as Inhibitors of African Swine Fever Virus Replication In Vitro . Antivir. Res. 8 (5-8), 273–281. 10.1016/S0166-3542(87)80005-0 PubMed DOI

Gilead (2022). Medicine. Available at: https://www.gilead.com/science-and-medicine/medicines .

Göbel R., Richter F., Weichmann H. (1992). Synthesis and Reactivity of Methylene Bridged Diphosphoryl Compounds. Phosphorus, Sulfur Silicon 73 (1-4), 67–80. 10.1080/10426509208034433 DOI

Gurkoff G. G., Feng J. F., Van K. C., Izadi A., Ghiasvand R., Shahlaie K., et al. (2013). NAAG Peptidase Inhibitor Improves Motor Function and Reduces Cognitive Dysfunction in a Model of TBI with Secondary Hypoxia. Brain Res. 1515, 98–107. 10.1016/j.brainres.2013.03.043 PubMed DOI PMC

Hatse S., Naesens L., De Clercq E., Balzarini J. (1999). N(6)-Cyclopropyl-PMEDAP: A Novel Derivative of 9-(2-Phosphonylmethoxyethyl)-2-6-Diaminopurine (PMEDAP) with Distinct Metabolic, Antiproliferative, and Differentiation-Inducing Properties. Biochem. Pharmacol. 58 (2), 311–323. 10.1016/S0006-2952(99)00091-X PubMed DOI

Heidel K. M., Dowd C. S. (2019). Phosphonate Prodrugs: an Overview and Recent Advances. Future Med. Chem. 11 (13), 1625–1643. 10.4155/fmc-2018-0591 PubMed DOI PMC

Herman B. D., Votruba I., Holý A., Sluis-Cremer N., Balzarini J. (2010). The Acyclic 2,4-diaminopyrimidine Nucleoside Phosphonate Acts as a Purine Mimetic in HIV-1 Reverse Transcriptase DNA Polymerization. J. Biol. Chem. 285 (16), 12101–12108. 10.1074/jbc.M109.096529 PubMed DOI PMC

Hézode C., Chevaliez S., Bouvier-Alias M., Roudot-Thoraval F., Brillet R., Zafrani E. S., et al. (2007). Efficacy and Safety of Adefovir Dipivoxil 20 Mg Daily in HBeAg-Positive Patients with Lamivudine-Resistant Hepatitis B Virus and a Suboptimal Virological Response to Adefovir Dipivoxil 10 Mg Daily. J. Hepatol. 46 (5), 791–796. 10.1016/j.jhep.2007.01.018 PubMed DOI

Hocková D., Holý A., Masojídková M., Andrei G., Snoeck R., De Clercq E., et al. (2003). 5-Substituted-2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]pyrimidines - Acyclic Nucleoside Phosphonate Analogues with Antiviral Activity. J. Med. Chem. 46 (23), 5064–5073. 10.1021/jm030932o PubMed DOI

Hocková D., Keough D. T., Janeba Z., Wang T.-H., De Jersey J., Guddat L. W. (2012). Synthesis of Novel N-Branched Acyclic Nucleoside Phosphonates as Potent and Selective Inhibitors of Human Plasmodium Falciparum and Plasmodium Vivax 6-oxopurine Phosphoribosyltransferases. J. Med. Chem. 55 (13), 6209–6223. 10.1021/jm300662d PubMed DOI

Hollinger K. R., Sharma A., Tallon C., Lovell L., Thomas A. G., Zhu X., et al. (2022). Dendrimer-2PMPA Selectively Blocks Upregulated Microglial GCPII Activity and Improves Cognition in a Mouse Model of Multiple Sclerosis. Nanotheranostics 6 (2), 126–142. 10.7150/ntno.63158 PubMed DOI PMC

Holý A., Dvořáková H., Jindřich J., Masojídková M., Buděšínský M., Balzarini J., et al. (1996). Acyclic Nucleotide Analogs Derived from 8-Azapurines: Synthesis and Antiviral Activity. J. Med. Chem. 39 (20), 4073–4088. 10.1021/jm960314q PubMed DOI

Holý A., Dvořáková H., Masojídková M. (1995). Synthesis of Enantiomeric N-(2-phosphonomethoxypropyl) Derivatives of Heterocyclic Bases. 2. Synthon Approach. Collect. Czech Chem. Commun. 60 (8), 1390–1409. 10.1135/cccc19951390 DOI

Holý A., Günter J., Dvořáková H., Masojídková G., Andrei G., Snoeck R., et al. (1999). Structure-antiviral Activity Relationship in the Series of Pyrimidine and Purine N-[2-(2- Phosphonomethoxy)ethyl] Nucleotide Analogues. 1. Derivatives Substituted at the Carbon Atoms of the Base. J. Med. Chem. 42 (12), 2064–2086. 10.1021/jm9811256 PubMed DOI

Holý A. (2003). Phosphonomethoxyalkyl Analogs of Nucleotides. Curr. Pharm. Des. 9 (31), 2567–2592. 10.2174/1381612033453668 PubMed DOI

Holý A., Rosenberg I., Dvořáková H. (1989). Synthesis of N-(2-phosphonylmethoxyethyl) Derivatives of Heterocyclic Bases. Collect. Czech Chem. Commun. 54 (8), 2190–2210. 10.1135/cccc19892190 DOI

Holý A. (1993). Syntheses of Enantiomeric N-(3-hydroxy-2-phosphonomethoxypropyl) Derivatives of Purine and Pyrimidine Bases. Collect. Czech Chem. Commun. 58 (3), 649–674. 10.1135/cccc19930649 DOI

Holý A. (2005). “Synthesis of Acyclic Nucleoside Phosphonates,” in Current Protocols In Nucleic Acid Chemistry”, 2005, Oct., Chapter 14, Unit 14.2, Hoboken, NJ, United States: John Wiley & Sons. 10.1002/0471142700.nc1402s22 PubMed DOI

Holý A., Votruba I., Masojídková M., Andrei G., Snoeck R., Naesens L., et al. (2002). 6-[2-(Phosphonomethoxy)alkoxy]pyrimidines with Antiviral Activity. J. Med. Chem. 45 (9), 1918–1929. 10.1021/jm011095y PubMed DOI

Holý A., Votruba I., Tloušťová E., Masojídková M. (2001). Synthesis and Cytostatic Activity of N-[2-(phosphonomethoxy)alkyl] Derivatives of N-6 Substituted Adenines, 2,6- Diaminopurines and Related Compounds. Collect. Czech Chem. Commun. 66 (10), 1545–1592. 10.1135/cccc20011545 DOI

Hostetler K. Y., Aldern K. A., Wan W. B., Ciesla S. L., Beadle J. R. (2006). Alkoxyalkylesters of (S)-HPMPA Are Potent Inhibitors of HIV-1 Replication, In Vitro . Antimicrob.Agents Chemother. 50, 2857–2859. PubMed PMC

Hostetler K. Y. (2009). Alkoxyalkyl Prodrugs of Acyclic Nucleoside Phosphonates Enhance Oral Antiviral Activity and Reduce Toxicity: Current State of the Art. Antivir. Res. 82 (2), A84–A98. 10.1016/j.antiviral.2009.01.005 PubMed DOI PMC

Izzedine H., Hulot J. S., Launay-Vacher V., Marcellini P., Hadziyannis S. J., Currie G., et al. (2004). Renal Safety of Adefovir Dipivoxil in Patients with Chronic Hepatitis B: Two Double-Blind, Randomized, Placebo-Controlled Studies. Kidney Int. 66 (3), 1153–1158. 10.1111/j.1523-1755.2004.00866.x PubMed DOI

Jackson P. F., Cole D. C., Slusher B. S., Stetz S. L., Ross L. E., Donzanti B. A., et al. (1996). Design, Synthesis, and Biological Activity of a Potent Inhibitor of the Neuropeptidase N-Acetylated Alpha-Linked Acidic Dipeptidase. J. Med. Chem. 39 (2), 619–622. 10.1021/jm950801q PubMed DOI

Jackson P. F., Slusher B. S. (2001). Design of NAALADase Inhibitors: A Novel Neuroprotective Strategy. Curr. Med. Chem. 8 (8), 949–957. 10.2174/0929867013372797 PubMed DOI

Jaffe I. A. (1986). Adverse Effects Profile of Sulfhydryl Compounds in Man. Am. J. Med. 80 (3), 471–476. 10.1016/0002-9343(86)90722-9 PubMed DOI

Janczura K. J., Olszewski R. T., Bzdega T., Bacich D. J., Heston W. D., Neale J. H. (2013). NAAG Peptidase Inhibitors and Deletion of NAAG Peptidase Gene Enhance Memory in Novel Object Recognition Test. Eur. J. Pharmacol. 701 (1-3), 27–32. 10.1016/j.ejphar.2012.11.027 PubMed DOI PMC

Jansa P., Baszczyňski O., Dračínský M., Votruba I., Zídek Z., Bahador G., et al. (2011). A Novel and Efficient One-Pot Synthesis of Symmetrical Diamide (Bis-amidate) Prodrugs of Acyclic Nucleoside Phosphonates and Evaluation of Their Biological Activities. Eur. J. Med. Chem. 46 (9), 3748–3754. 10.1016/j.ejmech.2011.05.040 PubMed DOI

Jindřich J., Holý A., Dvořáková H. (1993). Synthesis of N-(3-fluoro-2-phosphonomethoxypropyl) (FPMP) Derivatives of Heterocyclic Bases. Collect. Czech Chem. Commun. 58 (7), 1645–1667. 10.1135/cccc19931645 DOI

Jones D., J., O´Leary E., M., O´Sullivan T., P. (2019). An Improved Synthesis of Adefovir and Related Analogues. Beil. J. Org. Chem. 15, 801–810. 10.3762/bjoc.15.77 PubMed DOI PMC

Jones W., Griffiths K., Barata P. C., Paller C. J. (2020). PSMA Theranostics: Review of the Current Status of PSMA-Targeted Imaging and Radioligand Therapy. Cancers 12 (6), 1367. 10.3390/cancers12061367 PubMed DOI PMC

Jung Y. W., Kim M., Kim B. K., Park J. Y., Kim D., Ahn S. H., et al. (2020). Influence of Besifovir Dipivoxil Maleate Combined with L-Carnitine on Hepatic Steatosis in Patients with Chronic Hepatitis B. J. Korean Med. Sci. 35 (17), e104. 10.3346/jkms.2020.35.e104 PubMed DOI PMC

Kahn J., Lagakos S., Wulfsohn M., Cherng D., Miller M., Cherrington J., et al. (1999). Efficacy and Safety of Adefovir Dipivoxil with Antiretroviral Therapy: a Randomized Controlled Trial. JAMA- J. Am. Med. Assoc. 282 (24), 2305–2312. 10.1001/jama.282.24.2305 PubMed DOI

Kaittanis C., Andreou C., Hieronymus H., Mao N., Foss C. A., Eiber M., et al. (2018). Prostate-specific Membrane Antigen Cleavage of Vitamin B9 Stimulates Oncogenic Signaling through Metabotropic Glutamate Receptors. J. Exp. Med. 215 (1), 159–175. 10.1084/jem.20171052 PubMed DOI PMC

Kalčic F., Frydrych J., Doležalová E., Slapničková M., Pachl P., Poštová Slavětínská L., et al. (2021). C1 '-Branched Acyclic Nucleoside Phosphonates Mimicking Adenosine Monophosphate: Potent Inhibitors of Trypanosoma Brucei Adenine Phosphoribosyltransferase. Eur. J. Med. Chem. 225, 113798. 10.1016/j.ejmech.2021.113798 PubMed DOI

Kalčic F., Zgarbová M., Hodek J., Chalupský K., Dračínský M., Dvořáková A., et al. (2021). Discovery of Modified Amidate (ProTide) Prodrugs of Tenofovir with Enhanced Antiviral Properties. J. Med. Chem. 64 (22), 16425–16449. 10.1021/acs.jmedchem.1c01444 PubMed DOI

Kaminsky R., Schmid C., Grether Y., Holý A., De Clercq E., Naesens L., et al. (1996). (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA]: A Purine Analoguewith Trypanocidal Activity In Vitro and In Vivo . Trop. Med. Int. Health 1 (2), 255–263. 10.1111/j.1365-3156.1996.tb00036.x PubMed DOI

Kaminsky R., Zweygarth E., De Clercq E. (1994). Antitrypanosomal Activity of Phosphonomethoxyalkylpurines. J. Parasitol. 80 (6), 1026–1030. 10.2307/3283453 PubMed DOI

Keough D. T., Hocková D., Rejman D., Špaček P., Vrbková S., Krečmerová M., et al. (2013a). Inhibition of the Escherichia coli 6-Oxopurine Phosphoribosyltransferases by Nucleoside Phosphonates: Potential for New Antibacterial Agents. J. Med. Chem. 56 (17), 6967–6984. 10.1021/jm400779n PubMed DOI

Keough D. T., Rejman D., Pohl R., Zborníková E., Hocková D., Croll T., et al. (2018). Design of Plasmodium Vivax Hypoxanthine-Guanine Phosphoribosyltransferase Inhibitors as Potential Antimalarial Therapeutics. ACS Chem. Biol. 13 (1), 82–90. 10.1021/acschembio.7b00916 PubMed DOI

Keough D. T., Špaček P., Hocková D., Tichý T., Vrbková S., Slavětínská L., et al. (2013b). Acyclic Nucleoside Phosphonates Containing a Second Phosphonate Group Are Potent Inhibitors of 6-Oxopurine Phosphoribosyltransferases and Have Antimalarial Activity. J. Med. Chem. 56 (6), 2513–2526. 10.1021/jm301893b PubMed DOI

Kern E. R., Hartline C., Harden E., Keith K., Rodriguez N., Beadle J. R., et al. (2002). Enhanced Inhibition of Orthopoxvirus Replication In Vitro by Alkoxyalkyl Esters of Cidofovir and Cyclic Cidofovir. Antimicrob. Agents Chemother. 46 (4), 991–995. 10.1128/AAC.46.4.991-995.2002 PubMed DOI PMC

Kim D. H., Sung D. H., Min Y. K. (2013). Hypophosphatemic Osteomalacia Induced by Low-Dose Adefovir Therapy: Focus on Manifestations in the Skeletal System and Literature Review. J. Bone Min. Metab. 31 (2), 240–246. 10.1007/s00774-012-0384-y PubMed DOI

Klejch T., Keough D. T., Chavchich M., Travis J., Skácel J., Pohl R., et al. (2019). Sulfide, Sulfoxide and Sulfone Bridged Acyclic Nucleoside Phosphonates as Inhibitors of the Plasmodium Falciparum and Human 6-oxopurine Phosphoribosyltransferases: Synthesis Andevaluation. Eur. J. Med. Chem. 183, 111667. 10.1016/j.ejmech.2019.111667 PubMed DOI

Knejzlík Z., Herkommerová K., Hocková D., Pichová I. (2020). Hypoxanthine-Guanine Phosphoribosyltransferase Is Dispensable for Mycobacterium Smegmatis Viability. J. Bacteriol. 202 (5), e00710–19. 10.1128/JB.00710-19 PubMed DOI PMC

Kramata P., Downey K. M., Paborsky L. R. (1998). Incorporation and Excision of 9-(2- Phosphonylmethoxyethyl)guanine (PMEG) by DNA Polymerase Delta and Epsilon In Vitro . J. Biol. Chem. 273 (34), 21966–21971. 10.1074/jbc.273.34.21966 PubMed DOI

Kramata P., Votruba I., Otová B., Holý A. (1996). Different Inhibitory Potencies of Acyclic Phosphonomethoxyalkyl Nucleotide Analogs toward DNA Polymerases α, δ, and ε. Mol. Pharmacol. 49 (6), 1005 PubMed

Kratochwil C., Giesel F. L., Leotta K., Eder M., Hoppe-Tich T., Youssoufian H., et al. (2015). PMPA for Nephroprotection in PSMA-Targeted Radionuclide Therapy of Prostate Cancer. J. Nucl. Med. 56 (2), 293–298. 10.2967/jnumed.114.147181 PubMed DOI

Krečmerová M. (2017). Amino Acid Esters Prodrugs of Nucleoside and Nucleotide Antivirals. Mini Rev. Med. Chem. 17 (10), 818–833. 10.2174/1389557517666170216151601 PubMed DOI

Krečmerová M., Dračínský M., Hocková D., Holý A., Keough D. T., Guddat L. W. (2012). Synthesis of Purine N9-[2-Hydroxy-3-O-(phosphonomethoxy)propyl] Derivatives and Their Side-Chain Modified Analogues as Potential Antimalarial Agents. Bioorg. Med. Chem. 20 (3), 1222–1230. 10.1016/j.bmc.2011.12.034 PubMed DOI

Krečmerová M., Dračínský M., Snoeck R., Balzarini J., Pomeisl K., Andrei G. (2017). New Prodrugs of Two Pyrimidine Acyclic Nucleoside Phosphonates: Synthesis and Antiviral Activity. Bioorg. Med. Chem. 25 (17), 4637–4648. 10.1016/j.bmc.2017.06.046 PubMed DOI PMC

Krečmerová M., Holý A., Andrei G., Pomeisl K., Tichý T., Břehová P., et al. (2010). Synthesis of Ester Prodrugs of 9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine (HPMPDAP) as Anti-poxvirus Agents. J. Med. Chem. 53 (19), 6825–6837. 10.1021/jm901828c PubMed DOI

Krečmerová M., Holý A., Pískala A., Masojídková M., Andrei G., Naesens L., et al. (2007a). Antiviral Activity of Triazine Analogues of 1-(S)-[3- Hydroxy-2-(phosphonomethoxy)propyl]cytosine (Cidofovir) and Related Compounds. J. Med. Chem. 50 (5), 1069–1077. 10.1021/jm061281+ PubMed DOI

Krečmerová M., Holý A., Pohl R., Masojidková M., Andrei G., Naesens L., et al. (2007b). Ester Prodrugs of Cyclic 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine: Synthesis and Antiviral Activity. J. Med. Chem. 50 (23), 5765–5772. 10.1021/jm0707166 PubMed DOI

Krečmerová M., Jansa P., Dračínský M., Sázelová P., Kašička V., Neyts J., et al. (2013). 9-[2-(R)-(Phosphonomethoxy)propyl]-2,6-diaminopurine (R)-PMPDAP and its Prodrugs: Optimized Preparation, Including Identification of By-Products Formed, and Antiviral Evaluation In Vitro . Bioorg. Med. Chem. 21 (5), 1199–1208. 10.1016/j.bmc.2012.12.044 PubMed DOI PMC

Kreider J. W., Balogh K., Olson R. O., Martin J. C. (1990). Treatment of Latent Rabbit and Human Papillomavirus Infections with 9-(2-phosphonylmethoxy)ethylguanine (PMEG). Antivir. Res. 14 (1), 51–58. 10.1016/0166-3542(90)90065-F PubMed DOI

Krylov I. S., Kashemirov B. A., Hilfinger J. M., McKenna C. E. (2013). Evolution of an Amino Acid Based Prodrug Approach: Stay Tuned. Mol. Pharm. 10 (2), 445–458. 10.1021/mp300663j PubMed DOI PMC

Lacy S. A., Hitchcock M. J., Lee W. A., Tellier P., Cundy K. C. (1998). Effect of Oral Probenecid Coadministration on the Chronic Toxicity and Pharmacokinetics of Intravenous Cidofovir in Cynomolgus Monkeys. Toxicol. Sci. 44 (2), 97–106. 10.1006/toxs.1998.2481 PubMed DOI

Lee W. A., He G.-X., Eisenberg E., Cihlar T., Swaminathan S., Mulato A., et al. (2005). Selective Intracellular Activation of a Novel Prodrug of the Human Immunodeficiency Virus Reverse Transcriptase Inhibitor Tenofovir Leads to Preferential Distribution and Accumulation in Lymphatic Tissue. Antimicrob. Agents Chemother. 49 (5), 1898−1906. 10.1128/AAC.49.5.1898-1906.2005 PubMed DOI PMC

Liu D., Shi B., Wang F., Yu R., Hung C. (2013). Tenofovir Alafenamide hemifumarate. U.S. Patent No WO2013025788 A1. Foster City, CA, United States: Gilead Sciences, Inc. Publication date, 21.02. 2013.

Luo M., Groaz E., Andrei G., Snoeck R., Kalkeri R., Ptak R. G., et al. (2017). Expanding the Antiviral Spectrum of 3-Fluoro-2-(phosphonomethoxy)propyl Acyclic Nucleoside Phosphonates: Diamyl Aspartate Amidate Prodrugs. J. Med. Chem. 60 (14), 6220–6238. 10.1021/acs.jmedchem.7b00416 PubMed DOI

Luo M., Groaz E., De Jonghe S., Snoeck R., Andrei G., Herdewijn P. (2018). Amidate Prodrugs of Cyclic 9-(S)-[3-Hydroxy-2(phosphonomethoxy)propyl]adenine with Potent Anti-herpesvirus Activity. ACS Med. Chem. Lett. 9 (4), 381–385. 10.1021/acsmedchemlett.8b00079 PubMed DOI PMC

Luszczki J. J., Mohamed M., Czuczwar S. J. (2006). 2-phosphonomethyl-pentanedioic Acid (Glutamate Carboxypeptidase II Inhibitor) Increases Threshold for Electroconvulsionsions and Enhances the Antiseizure Action of Valproate against Maximal Electroshock-Induced Seizures in Mice. Eur. J. Pharmacol. 531 (1-3), 66–73. 10.1016/j.ejphar.2005.11.045 PubMed DOI

Lyseng-Williamson K. A., Reynolds N. A., Plosker G. L. (2005). Tenofovir Disoproxil Fumarate - A Review of its Use in the Management of HIV Infection. Drugs 65 (3), 413–432. 10.2165/00003495-200565030-00006 PubMed DOI

Majer P., Jackson P. F., Delahanty G., Grella B. S., Ko Y. S., Li W., et al. (2003). Synthesis and Biological Evaluation of Thiol-Based Inhibitors of Glutamate Carboxypeptidase II: Discovery of an Orally Active GCP II Inhibitor. J. Med. Chem. 46 (10), 1989–1996. 10.1021/jm020515w PubMed DOI

Majer P., Jančařík A., Krečmerová M., Tichý T., Tenora L., Wozniak K., et al. (2016). Discovery of Orally Available Prodrugs of the Glutamate Carboxypeptidase II (GCP II) Inhibitor 2-phosphonomethyl Pentanedioic Acid (2-PMPA). J. Med. Chem. 59 (6), 2810–2819. 10.1021/acs.jmedchem.6b00062 PubMed DOI

Marrazzo J. M., Ramjee G., Richardson B. A., Gomez K., Mgodi N. M., Nair G., et al. (2015). Tenofovir-based Preexposure Prophylaxis for HIV Infection Among African Women. N. Engl. J. Med. 372 (6), 509–518. 10.1056/NEJMoa1402269 PubMed DOI PMC

Marty F. M., Winston D. J., Chemaly R. F., Mullane K. M., Shore T. B., Papanicolaou G. A., et al. (2019). A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial of Oral Brincidofovir for Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Cell Transplantation. Biol. Blood Marrow Transpl. 25 (2), 369–381. 10.1016/j.bbmt.2018.09.038 PubMed DOI PMC

McKinzie D. L., Li T. K., McBride W. J., Slusher B. S. (2000). NAALADase Inhibition Reduces Alcohol Consumption in the Alcohol‐preferring (P) Line of Rats. Addict. Biol. 5 (4), 411–416. 10.1111/j.1369-1600.2000.tb00209.x PubMed DOI

Meier C., Balzarini J. (2006). Application of the Sal-Prodrug Approach for Improving the Biological Potential of Phosphorylated Biomolecules. Antivir. Res. 71 (2-3), 282–292. 10.1016/j.antiviral.2006.04.011 PubMed DOI

Meier C. (2006). CycloSal Phosphates as Chemical Trojan Horses for Intracellular Nucleotide and Glycosylmonophosphate Delivery - Chemistry Meets Biology. Eur. J. Org. Chem. (5), 1081–1102. 10.1002/ejoc.200500671 DOI

Meier C., Görbig U., Müller C., Balzarini C. (2005). cycloSal-PMEA and cycloAmb-PMEA: Potentially New Phosphonate Prodrugs Based on the cycloSal-Pronucleotide Approach. J. Med. Chem. 48 (25), 8079–8086. 10.1021/jm050641a PubMed DOI

Murata K., Tsukuda S., Suizu F., Kimura A., Sugiyama S., Watashi K., et al. (2020). Immunomodulatory Mechanism of Acyclic Nucleoside Phosphates in Treatment of Hepatitis B Virus Infection. Hepatology 71 (5), 1533–1545. 10.1002/hep.30956 PubMed DOI

Nachega J. B., Uthman O. A., Mofenson L. M., Anderson J. R., Kanters S., Renaud F., et al. (2017). Safety of Tenofovir Disoproxil Fumarate-Based Antiretroviral Therapy Regimens in Pregnancy for HIV-Infected Women and Their Infants: A Systematic Review and Meta Analysis. J. Acquir Immune Defic. Syndr. 76 (1), 1–12. 10.1097/qai.0000000000001359 PubMed DOI PMC

Naesens L., Andrei G., Votruba I., Krečmerová M., Holý A., Neyts J., et al. (2008). Intracellular Metabolism of the New Antiviral Compound, 1-(S)-[3-hydroxy-2--(phosphonomethoxy)propyl]-5-azacytosine. Biochem. Pharmacol. 76 (8), 997–1005. 10.1016/j.bcp.2008.08.009 PubMed DOI

Naesens L., Balzarini J., De Clercq E. (1994). Therapeutic Potential of PMEA as an Antiviral Drug. Rev. Med. Virol. 4 (3), 147–159. 10.1002/rmv.1980040302 DOI

Najjar A., Karaman R. (2019). The Prodrug Approach in the Era of Drug Design. Expert Opin. Drug Del 16 (1), 1–5. 10.1080/17425247.2019.1553954 PubMed DOI

Neale J. H., Yamamoto T. (2020). N-acetylaspartylglutamate (NAAG) and Glutamate Carboxypeptidase II: An Abundant Peptide Neurotransmitter-Enzyme System with Multiple Clinical Applications. Prog. Neurobiol. 184, 101722. 10.1016/j.pneurobio.2019.101722 PubMed DOI

Neant N., Klifa R., Bouazza N., Moshous D., Neven B., Leruez-Ville B., et al. (2018). Model of Population Pharmacokinetics of Cidofovir in Immunocompromised Children with Cytomegalovirus and Adenovirus Infections. J. Antimicrob. Chemother. 73 (9), 2422–2429. 10.1093/jac/dky192 PubMed DOI

Nedelcovych M., Dash R. P., Tenora L., Zimmermann S. C., Gadiano A. J., Garrett C., et al. (2017). Enhanced Brain Delivery of 2-(Phosphonomethyl)pentanedioic Acid Following Intranasal Administration of its γ-Substituted Ester Prodrugs. Mol. Pharm. 14 (10), 3248–3257. 10.1021/acs.molpharmaceut.7b00231 PubMed DOI PMC

Neofytos D., Ojha A., Mookerjee B., Wagner J., Filicko J., Ferber A., et al. (2007). Treatment of Adenovirus Disease in Stem Cell Transplant Recipients with Cidofovir. Biol. Blood Marrow Transpl. 13 (1), 74–81. 10.1016/j.bbmt.2006.08.040 PubMed DOI

Nguyen T., Kirsch B. J., Asaka R., Nabi K., Quinones A., Tan J., et al. (2019). Uncovering the Role of N-Acetyl-Aspartyl-Glutamate as a Glutamate Reservoir in Cancer. Cell Rep. 27 (2), 491–501. 10.1016/j.celrep.2019.03.036 PubMed DOI PMC

Nonaka T., Yamada T., Ishimura T., Zuo D. Y., Moffett J. R., Neale J. H., et al. (2017). A Role for the Locus Coeruleus in the Analgesic Efficacy of N-Acetylaspartylglutamate Peptidase (GCPII) Inhibitors ZJ43 and 2-PMPA. Mol. Pain 13, 1–13. 10.1177/1744806917697008 PubMed DOI PMC

Oh C. H., Hong J. H. (2008). Design, Synthesis and Anti-HIV Activity of Homologous PMEA Derivatives. Nucleosides Nucleotides Nucleic Acids 27 (2), 186–195. 10.1080/15257770701795953 PubMed DOI

Olszewski R. T., Janczura K. J., Ball S. R., Madore J. C., Lavin K. M., Lee J. C., et al. (2012). NAAG Peptidase Inhibitors Block Cognitive Deficit Induced by MK-801 and Motor Activation Induced by D-Amphetamine in Animal Models of Schizophrenia. TranslPsychiatry 2, e145. 10.1038/tp.2012.68 PubMed DOI PMC

Olszewski R. T., Janczura K. J., Bzdega T., Der E. K., Venzor F., O´Rourke B., et al. (2017). NAAG Peptidase Inhibitors Act via mGluR3: Animal Models of Memory, Alzheimer's, and Ethanol Intoxication. Neurochem. Res. 42 (9), 2646–2657. 10.1007/s11064-017-2181-4 PubMed DOI PMC

Park S., Kim W. I., Cho D.-H., Kim Y. J., Kim H. S., Kim J. H., et al. (2018). Adefovir-induced Fanconi Syndrome Associated with Osteomalacia. Clin. Mol. Hepatol. 24 (3), 339–344. 10.3350/cmh.2017.0009 PubMed DOI

Peters D. E., Norris L. D., Slusher B. S. (2019). Spontaneous Loss-Of-Function Dock2 Mutation Alters Murine Colitis Sensitivity and Is a Confounding Variable in Inflammatory Bowel Disease Research. Crohn's Colitis 360, otz030. 10.1093/crocol/otz030 DOI

Peters D., Norris L., Tenora L., Šnajdr I., Zhu X., Sakamoto S., et al. (2022). Discovery of IBD3540: A Novel Gut-Restricted Glutamate Carboxypeptidase II Inhibitor with Oral Activity in Mouse Colitis Models. Inflam. Bowel Dis. 28 (Suppl. 1), S4. 10.1093/ibd/izac015.007 DOI

Peterson L. W., Kim J. S., Kijek P., Mitchell S., Hilfinger J. M., Breitenbach J. M., et al. (2011). Synthesis, Transport and Antiviral Activity of Ala-Ser and Val-Ser Prodrugs of Cidofovir. Bioorg. Med. Chem. Lett. 21 (13), 4045–4049. 10.1016/j.bmcl.2011.04.126 PubMed DOI PMC

Pisarev V. M., Lee S.-H., Connelly M. C., Fridland A. (1997). Intracellular Metabolism and Action of Acyclic Nucleoside Phosphonates on DNA Replication. Mol. Pharmacol. 52 (1), 63–68. 10.1124/mol.52.1.63 PubMed DOI

Plosker G. L., Noble S. (1999). Cidofovir - A Review of its Use in Cytomegalovirus Retinitis in Patients with AIDS. Drugs 58 (2), 325–345. 10.2165/00003495-199958020-00015 PubMed DOI

Pomeisl K., Pohl R., Holý A., Votruba I. (2005). Simple Transformation of Thymine 1-[3-hydroxy-2-(phosphonomethoxy)propyl] Derivatives to Their 1-[3-fluoro-2-(phosphonomethoxy)propyl] Counterparts. Collect. Czech Chem. Commun. 70 (9), 1465–1481. 10.1135/cccc20051465 DOI

Pomeislová A., Otmar M., Rubešová P., Benýšek J., Matoušová M., Mertlíková-Kaiserová H., et al. (2021). 1,2,4-Thiadiazole Acyclic Nucleoside Phosphonates as Inhibitors of Cysteine Dependent Enzymes Cathepsin K and GSK-3β. Bioorg. Med. Chem. 32, 115998. 10.1016/j.bmc.2021.115998 PubMed DOI

Pradere U., Garnier-Amblard E. C., Coats S. J., Amblard F., Schinazi R. F. (2014). Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs. Chem. Rev. 114 (18), 9154–9218. 10.1021/cr5002035 PubMed DOI PMC

Rahn K. A., Watkins C. C., Alt J., Rais R., Stathis M., Grishkan I., et al. (2012). Inhibition of Glutamate Carboxypeptidase II (GCPII) Activity as a Treatment for Cognitive Impairment in Multiple Sclerosis. Proc. Natl. Acad. Sci. U. S. A. 109 (49), 20101–20106. 10.1073/pnas.1209934109 PubMed DOI PMC

Rais R., Jiang W. W., Zhai H. H., Wozniak K. M., Stathis M., Hollinger K. R., et al. (2016). FOLH1/GCPII Is Elevated in IBD Patients, and its Inhibition Ameliorates Murine IBD Abnormalities. JCI Insight 1 (12), e88634. 10.1172/jci.insight.88634 PubMed DOI PMC

Rais R., Wozniak K., Wu Y., Niwa M., Stathis M., Alt J., et al. (2015). Selective CNS Uptake of the GCP-II Inhibitor 2-PMPA Following Intranasal Administration. Plos One 10 (7), e0131861. 10.1371/journal.pone.0131861 PubMed DOI PMC

Ramanathan S. (2013). Combination Therapy Comprising Tenofovir Alafenamide Hemifumarate and Cobicistat for Use in the Treatment of Viral Infections. Foster City, CA, United States: Gilead Sciences, Inc. Publication date. U.S. Patent No. WO/2013/116730-08-08.

Rautio J., Kumpulainen H., Heimbach T., Oliyai R., Oh D., Järvinen T., et al. (2008). Prodrugs: Design and Clinical Applications. Nat. Rev. Drug Discov. 7 (3), 255–270. 10.1038/nrd2468 PubMed DOI

Reddy K. R., Matelich M. C., Ugarkar B. G., Gomez-Galeno J. E., DaRe J., Ollis K., et al. (2008). Pradefovir: A Prodrug that Targets Adefovir to the Liver for the Treatment of Hepatitis B. J. Med. Chem. 51 (3), 666–676. 10.1021/jm7012216 PubMed DOI

Reiser H., Wang J. Y., Chong L., Watkins W. J., Ray A. S., Shibata R., et al. (2008). GS-9219 - A Novel Acyclic Nucleotide Analogue with Potent Antineoplastic Activity in Dogs with Spontaneous Non–hodgkin's Lymphoma. Clin. Cancer Res. 14 (9), 2824–2832. 10.1158/1078-0432.CCR-07-2061 PubMed DOI

Reymen D., Naesens L., Balzarini J., Holý A., Dvořáková H., De Clercq E. (1995). Antiviral Activity of Selected Acyclic Nucleoside Analogues against Human Herpesvirus 6. Antivir. Res. 28 (4), 343–357. 10.1016/0166-3542(95)00058-5 PubMed DOI

Roels S., Van der Heyden S., Neyts J., Krečmerová M., Koenen F., Cay A. B., et al. (2013). Safety Assessment in Pigs of an Experimental Molecule with In-Vitro Antiviral Activity against African Swine Fever. J. Comp. Pathol. 148 (1), 94. 10.1016/j.jcpa.2012.11.194 DOI

Rose W. C., Crosswell A. R., Bronson J. J., Martin J. C. (1990). In Vivo tumor Activity of 9-[(2-Phosphonylmethoxy)ethyl]-Guanine (PMEG) and Related Phosphonate Nucleotide Analogs. J. Natl. Cancer Inst. 82 (6), 510–512. 10.1093/jnci/82.6.510 PubMed DOI

Ruiz J., Beadle J. R., Buller R. M., Schreiwer J., Prichard M. N., Keith K. A., et al. (2011). Synthesis, Metabolic Stability and Antiviral Evaluation of Various Alkoxyalkyl Esters of Cidofovir and 9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine. Bioorg. Med. Chem. 19 (9), 2950–2958. 10.1016/j.bmc.2011.03.034 PubMed DOI PMC

Schinkmanová M., Votruba I., Holý A. (2006). N-6-Methyl-AMP Aminohydrolase Activates N-6-Substituted Purine Acyclic Nucleoside Phosphonates. Biochem. Pharmacol. 71 (9), 1370–1376. 10.1016/j.bcp.2006.01.013 PubMed DOI

Schinkmanová M., Votruba I., Shibata R., Han B., Liu X. H., Cihlář T., et al. (2008). Human N-6-Methyl-AMP/damp Aminohydrolase (Abacavir 5 '-monophosphate Deaminase) Is Capable of Metabolizing N-6-Substituted Purine Acyclic Nucleoside Phosphonates. Collect. Czech. Chem. Commun. 73 (2), 275–291. 10.1135/cccc20080275 DOI

Seley-Radtke K. L., Yates M. K. (2018). The Evolution of Nucleoside Analogue Antivirals: A Review for Chemists and Non-chemists. Part 1: Early Structural Modifications to the Nucleoside Scaffold. Antivir. Res. 154, 66–86. 10.1016/j.antiviral.2018.04.004 PubMed DOI PMC

Shaw J. P., Louie M. S., Krishnamurty V. V., Arimilli M. N., Jones R. J., Bidgood A. M., et al. (1997). Pharmacokinetics and Metabolism of Selected Prodrugs of PMEA in Rats. Drug Metab. Dispos. 25 (3), 362 PubMed

Siberry G. K., Williams P. L., Mendez H., Seage G. R., III, Jacobson D. L., Hazra R., et al. (2012). Safety of Tenofovir Use during Pregnancy: Early Growth Outcomes in HIV-Exposed Uninfected Infants. AIDS 26 (9), 1151–1159. 10.1097/QAD.0b013e328352d135 PubMed DOI PMC

Slusher B. S., Robinson M. B., Tsai G. C., Simmons M. L., Richards S. S., Coyle J. T. (1990). Rat-brain N-Acetylated Alpha-Linked Acidic Dipeptidase Activity – Purification and Immunological Characterization. J. Biol. Chem. 265 (34), 21297–21301. 10.1016/s0021-9258(17)45359-2 PubMed DOI

Slusher B. S., Vornov J. J., Thomas A. G., Hurn P. D., Harukuni I., Bhardwaj A., et al. (1999). Selective Inhibition of NAALADase, Which Converts NAAG to Glutamate, Reduces Ischemic Brain Injury. Nat. Med. 5 (12), 1396–1402. 10.1038/70971 PubMed DOI

Šmídková M., Dvořáková A., Tloušťová E., Česnek M., Janeba Z., Mertlíková-Kaiserová H. (2014). Amidate Prodrugs of 9-[2-(phosphonomethoxy)ethyl]adenine as Inhibitors of Adenylate Cyclase Toxin from Bordetella Pertusis. Antimicrob. Agents Chemother. 58 (2), 664–671. 10.1128/AAC.01685-13 PubMed DOI PMC

Smith W. R., Neill J., Cushman W. C., Butkus D. E. (1989). Captopril-Associated Acute Interstitial Nephritis. Am. J. Nephrol. 9 (3), 230–235. 10.1159/000167970 PubMed DOI

Srinivas R. V., Fridland A. (1998). Antiviral Activities of 9-R-2-Phosphonomethoxypropyl Adenine (PMPA) and Bis(isopropyloxymethylcarbonyl) PMPA against Various Drug-Resistant Human Immunodeficiency Virus Strains. Antimicrob. Agents Chemother. 42 (6), 1484–1487. 10.1128/AAC.42.6.1484 PubMed DOI PMC

Starrett J. E., Jr., Tortolani D. R., Hitchcock M. J., Martin J. C., Mansuri M. M. (1992). Synthesis and in Evaluation of a Phosphonate Prodrug: Bis(pivaloyloxymethyl) 9-(2- Phosphonylmethoxyethyl)adenine. Antivir. Res. 19 (3), 267–273. 10.1016/0166-3542(92)90084-I PubMed DOI

Stoermer D., Liu Q., Hall M. R., Flanary J. M., Thomas A. G., Rojas C., et al. (2003). Synthesis and Biological Evaluation of Hydroxamate-Based Inhibitors of Glutamate Carboxypeptidase II. Bioorg. Med. Chem. Lett. 13 (13), 2097–2100. 10.1016/S0960-894X(03)00407-4 PubMed DOI

Suo Z., Johnson K. A. (1998). Selective Inhibition of HIV-1 Reverse Transcriptase by an Antiviral Inhibitor, (R)-9-(2-Phosphonylmethoxypropyl) Adenine. J. Biol. Chem. 273 (42), 27250–27258. 10.1074/jbc.273.42.27250 PubMed DOI

Taffin E., Paepe D., Goris N., Auwerx J., Debille M., Neyts J., et al. (2015). Antiviral Treatment of Feline Immunodeficiency Virus-Infected Cats with (R)-9-(2- Phosphonylmethoxypropyl)-2,6-Diaminopurine. L. Feline Med. Surg. 17 (2), 79–86. 10.1177/1098612X14532089 PubMed DOI PMC

Tallon C., Sharma A., Zhang Z., Thomas A: G., Ng J., Zhu X. L., et al. (2022). Dendrimer-2PMPA Delays Muscle Function Loss and Denervation in a Murine Model of Amyotrophic Lateral Sclerosis. Neurotherapeutics 1, 15. 10.1007/s13311-021-01159-7 PubMed DOI PMC

Teran D. (2020). Acyclic Nucleoside Phosphonates as Possible Chemotherapeutics against Trypanosoma Brucei. Drug Discov. Today 25 (6), 1043–1053. 10.1016/j.drudis.2020.02.008 PubMed DOI

Tillmann H. L. (2007). Drug Evaluation: Pradefovir, a Liver-Targeted Prodrug of Adefovir against HBV Infection. Curr. Opin. Invest.. Drugs 8 (8), 682. PubMed

Tillmann H. L., Samuel G. (2019). Current State-Of-The-Art Pharmacotherapy for the Management of Hepatitis B Infection. Expert Opin. Pharmacother. 20 (7), 873–885. 10.1080/14656566.2019.1583744 PubMed DOI

Vahlenkamp T. W., Deronde A., Balzarini J., Naesens L., De Clercq E., Vaneijk M. J. T., et al. (1995). (R)-9-(2-phosphonylmethoxypropyl)-2,6-diaminopurine Is a Potent Inhibitor of Feline Immunodeficiency Virus-Infection. Antimicrob. Agents Chemother. 39 (3), 746–749. 10.1128/AAC.39.3.746 PubMed DOI PMC

Valiaeva N., Prichard M. N., Buller R. M., Beadle J. R., Hartline C. B., Keith K. A., et al. (2009). Antiviral Evaluation of Octadecyloxyethyl Esters of (S)-3-hydroxy-2-(phosphonomethoxy)propyl Nucleosides against Herpesviruses and Orthopoxviruses. Antivir. Res. 84 (3), 254–259. 10.1016/j.antiviral.2009.09.012 PubMed DOI PMC

Valiaeva N., Wyles D. L., Schooley R. T., Hwu J. B., et al. (2006). Synthesis and Antiviral Evaluation of 9-(S)-[3-alkoxy-2--(phosphonomethoxy)propyl]nucleoside Alkoxyalkyl Esters: Inhibitors of Hepatitis C Virus and HIV-1 Replication. Bioorg. Med. Chem. 19 (15), 4616–4625. 10.1016/j.bmc.2011.06.009 PubMed DOI PMC

Van Damme L., Corneli A., Ahmed K., Agot K., Lombaard J., Kapiga S., et al. (2012). Preexposure Prophylaxis for HIV Infection Among African Women. N. Engl. J. Med. 367 (5), 411–422. 10.1056/NEJMoa1202614 PubMed DOI PMC

van der Post J. P., de Visser S. J., de Kam M. L., Woelfler M., Hilt D. C., Vornov J., et al. (2005). The Central Nervous System Effects, Pharmacokinetics and Safety of the NAALADase-Inhibitor GPI 5693. Br. J. Clin. Pharmacol. 60 (2), 128–136. 10.1111/j.1365-2125.2005.02396.x PubMed DOI PMC

van Gelder J., Deferme S., Naesens L., De Clercq E., van den Mooter G., Kinget R., et al. (2002). Intestinal Absorption Enhancement of the Ester Prodrug Tenofovir Disoproxil Fumarate through Modulation of the Biochemical Barrier by Defined Ester Mixtures. Drug. Metab. Dispos. 30 (8), 924–930. 10.1124/dmd.30.8.924 PubMed DOI

Vornov J. J., Hollinger K. R., Jackson P. F., Wozniak K. M., Farah M. H., Majer P., et al. (2016). Still NAAG’ing after All These Years: the Continuing Pursuit of GCPII Inhibitors. Adv. Pharmacol. 76, 215–255. 10.1016/bs.apha.2016.01.007 PubMed DOI

Vornov J. J., Wozniak K. M., Wu Y., Rojas C., Rais R., Slusher B. S. (2013). Pharmacokinetics and Pharmacodynamics of the Glutamate Carboxypeptidase II Inhibitor 2-MPPA Show Prolonged Alleviation of Neuropathic Pain through an Indirect Mechanism. J. Pharmacol. Exp. Ther. 346 (3), 406–413. 10.1124/jpet.113.205039 PubMed DOI PMC

Votruba I., Tryznová J., Břehová P., Tloušťová E., Horská K., Fanfrlík J., et al. (2010). Inhibition of Human Purine Nucleoside Phosphorylase by Tenofovir Phosphate Congeners. Collect. Czech Chem. Commun. 75 (12), 1249–1257. 10.1135/cccc2010094 DOI

Wang L. M., Kourtis A. P., Ellington S., Legardy-Williams J., Bulterys M. (2013). Safety of Tenofovir during Pregnancy for the Mother and Fetus: A Systematic Review. Clin. Infect. Dis. 57 (12), 1773–1781. 10.1093/cid/cit601 PubMed DOI

Wang R. X., Lin L. Y., Zheng Y. Q., Cao P., Yuchi Z. G., Wu H. Y. (2020). Identification of 2-PMPA as a Novel Inhibitor of Cytosolic Carboxypeptidases. Biochem. Biophys. Res. Commun. 533 (4), 1393–1399. 10.1016/j.bbrc.2020.10.029 PubMed DOI

Williams M., Krylov I. S., Zakharova V. M., Serpi M., Peterson L. W., Krečmerová M., et al. (2011). Cyclic and Acyclic Phosphonate Tyrosine Ester Prodrugs of Acyclic Nucleoside Phosphonates.”in Collect. Symp. Ser. Editor Hocek M., 12, 167. Institute of Organic Chemistry and Biochemistry, ASCR, Prague: .10.1135/css201112167 DOI

Wolf D. L., Rodriguez C. A., Mucci M., Ingrosso A., Duncan B. A., Nickens D. J. (2003). Pharmacokinetics and Renal Effects of Cidofovir with a Reduced Dose of Probenecid in HIV-Infected Patients with Cytomegalovirus Retinitis. J. Clin. Pharmacol. 43 (1), 43–51. 10.1177/0091270002239705 PubMed DOI

Wyles D. L., Kaihara K. A., Korba B. E., Schooley R. T., et al. (2009). The Octadecyloxyethyl Ester of (S)-9-[3-Hydroxy-2-(Phosphonomethoxy) Propyl]Adenine Is a Potent and Selective Inhibitor of Hepatitis C Virus Replication in Genotype 1A, 1B, and 2A Replicons. Antimicrob. Agents Chemother. 53 (6), 2660–2662. 10.1128/aac.01546-08 PubMed DOI PMC

Xi Z. X., Li X., Peng X. Q., Li J., Chun L., Gardner E. L., et al. (2010). Inhibition of NAALADase by 2-PMPA Attenuates Cocaine-Induced Relapse in Rats: a NAAG-mGluR2/3-Mediated Mechanism. J. Neurochem. 112 (2), 564–576. 10.1111/j.1471-4159.2009.06478.x PubMed DOI PMC

Yang D. H., Xie Y. J., Zhao N. F., Pan H. Y., Li M. W., Huang H. J. (2015). Tenofovir Disoproxil Fumarate Is Superior to Lamivudine Plus Adefovir in Lamivudine-Resistant Chronic Hepatitis B Patients. World J. Gastroenterol. 21 (9), 2746–2753. 10.3748/wjg.v21.i9.2746 PubMed DOI PMC

Yim H. J., Kim W., Ahn S. H., Yang J. M., Jang J. Y., Kweon Y. O., et al. (2020). Besifovir Dipivoxil Maleate 144-Week Treatment of Chronic Hepatitis B: An Open-Label Extensional Study of a Phase 3 Trial. Am. J. Gastroenterol. 115 (8), 1217–1225. 10.14309/ajg.0000000000000605 PubMed DOI PMC

Zakharova V. M., Serpi M., Krylov I. S., Peterson L. W., Breitenbach J. M., Borysko K. Z., et al. (2011). Tyrosine-Based 1-(S)-[3-Hydroxy-2-(phosphonomethoxy)propyl]cytosine and -adenine ((S)-HPMPC and (S)-HPMPA) Prodrugs: Synthesis, Stability, Antiviral Activity, and In Vivo Transport Studies. J. Med. Chem. 54 (16), 5680–5693. 10.1021/jm2001426 PubMed DOI PMC

Zhang H. B., Koumna S., Pouliot F., Beauregard J. M., Kolinsky M. (2021). PSMA Theranostics: Current Landscape and Future Outlook. Cancers 13 (16), 4023. 10.3390/cancers13164023 PubMed DOI PMC

Zhang H., Wu M., Zhu X. X., Li C. Y., Li X. J., Jin W. L., et al. (2020). Safety, Efficacy, and Pharmacokinetics of Pradefovir for the Treatment of Chronic Hepatitis B Infection. Antivir. Res. 174, 104693. 10.1016/j.antiviral.2019.104693 PubMed DOI

Zhang W., Murakawa Y., Wozniak K. M., Slusher B., Sima A. A. (2006). The Preventive and Therapeutic Effects of GCPII (NAALADase) Inhibition on Painful and Sensory Diabetic Neuropathy. J. Neurol. Sci. 247 (2), 217–223. 10.1016/j.jns.2006.05.052 PubMed DOI

Zhang W., Slusher B., Murakawa Y., Wozniak K. M., Tsukamoto T., Jackson P., et al. (2002). A. GCPII (NAALADase) Inhibition Prevents Long-Term Diabetic Neuropathy in Type 1 Diabetic BB/Wor Rats. J. Neurol. Sci. 194 (1), 21–28. 10.1016/S0022-510X(01)00670-0 PubMed DOI

Zhang Z., Bassam B., Thomas A. G., Williams M., Liu J. H., Nance E., et al. (2016). Maternal Inflammation Leads to Impaired Glutamate Homeostasis and Up-Regulation of Glutamate Carboxypeptidase II in Activated Microglia in the Fetal/newborn Rabbit Brain. Neurobiol. Dis. 94, 116–128. 10.1016/j.nbd.2016.06.010 PubMed DOI PMC

Pro-905, a Novel Purine Antimetabolite, Combines with Glutamine Amidotransferase Inhibition to Suppress Growth of Malignant Peripheral Nerve Sheath Tumor