Psoromic acid (PA), a bioactive lichen-derived compound, was investigated for its inhibitory properties against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), along with the inhibitory effect on HSV-1 DNA polymerase, which is a key enzyme that plays an essential role in HSV-1 replication cycle. PA was found to notably inhibit HSV-1 replication (50% inhibitory concentration (IC50): 1.9 μM; selectivity index (SI): 163.2) compared with the standard drug acyclovir (ACV) (IC50: 2.6 μM; SI: 119.2). The combination of PA with ACV has led to potent inhibitory activity against HSV-1 replication (IC50: 1.1 µM; SI: 281.8) compared with that of ACV. Moreover, PA displayed equivalent inhibitory action against HSV-2 replication (50% effective concentration (EC50): 2.7 μM; SI: 114.8) compared with that of ACV (EC50: 2.8 μM; SI: 110.7). The inhibition potency of PA in combination with ACV against HSV-2 replication was also detected (EC50: 1.8 µM; SI: 172.2). Further, PA was observed to effectively inhibit HSV-1 DNA polymerase (as a non-nucleoside inhibitor) with respect to dTTP incorporation in a competitive inhibition mode (half maximal inhibitory concentration (IC50): 0.7 μM; inhibition constant (Ki): 0.3 μM) compared with reference drugs aphidicolin (IC50: 0.8 μM; Ki: 0.4 μM) and ACV triphosphate (ACV-TP) (IC50: 0.9 μM; Ki: 0.5 μM). It is noteworthy that the mechanism by which PA-induced anti-HSV-1 activity was related to its inhibitory action against HSV-1 DNA polymerase. Furthermore, the outcomes of in vitro experiments were authenticated using molecular docking analyses, as the molecular interactions of PA with the active sites of HSV-1 DNA polymerase and HSV-2 protease (an essential enzyme required for HSV-2 replication) were revealed. Since this is a first report on the above-mentioned properties, we can conclude that PA might be a future drug for the treatment of HSV infections as well as a promising lead molecule for further anti-HSV drug design.

Departamento de Ciencias del Ambiente Facultad de Química y Biología Universidad de Santiago de Chile Casilla 40 Correo 33 Santiago 9170022 Chile

Department of Applied Ecology Faculty of Environmental Sciences Czech University of Life Sciences Prague Kamýcká 129 165 21 Praha 6 Suchdol Czech Republic

Department of Natural Drugs Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences Brno Palackého tř 1946 1 612 42 Brno Czech Republic

Museum of Literature in Moravia Klášter 1 664 61 Rajhrad Czech Republic

See more in PubMed

Hassan S.T., Masarčíková R., Berchová K. Bioactive natural products with anti-herpes simplex virus properties. J. Pharm. Pharmacol. 2015;67:1325–1336. doi: 10.1111/jphp.12436. PubMed DOI

Kobty M. Herpes Simplex Virus: Beyond the Basics. Neonatal Netw. 2015;34:279–283. doi: 10.1891/0730-0832.34.5.279. PubMed DOI

Sanders J.E., Garcia S.E. Pediatric herpes simplex virus infections: An evidence-based approach to treatment. Pediatr. Emerg. Med. Pract. 2014;11:1–19. PubMed

Miller A.S., Bennett J.S. Challenges in the care of young infants with suspected neonatal herpes simplex virus. Hosp. Pediatr. 2015;5:106–108. doi: 10.1542/hpeds.2014-0095. PubMed DOI

Widener R.W., Whitley R.J. Herpes simplex virus. Handb. Clin. Neurol. 2014;123:251–263. PubMed

Akinyi B., Odhiambo C., Otieno F., Inzaule S., Oswago S., Kerubo E., Ndivo R., Zeh C. Prevalence, incidence and correlates of HSV-2 infection in an HIV incidence adolescent and adult cohort study in western Kenya. PLoS ONE. 2017;12:e0178907. doi: 10.1371/journal.pone.0178907. PubMed DOI PMC

Memish Z.A., Almasri M., Chentoufi A.A., Al-Tawfiq J.A., Al-Shangiti A.M., Al-Kabbani K.M., Otaibi B., Assirri A., Yezli S. Seroprevalence of Herpes Simplex Virus Type 1 and Type 2 and Coinfection with HIV and Syphilis: The First National Seroprevalence Survey in Saudi Arabia. Sex. Trans. Dis. 2015;42:526–532. doi: 10.1097/OLQ.0000000000000336. PubMed DOI

Koyuncu O.O., MacGibeny M.A., Enquist L.W. Latent versus productive infection: The alpha herpesvirus switch. Future Virol. 2018;13:431–443. doi: 10.2217/fvl-2018-0023. PubMed DOI PMC

Knipe D.M., Cliffe A. Chromatin control of herpes simplex virus lytic and latent infection. Nat. Rev. Microbiol. 2008;6:211–221. doi: 10.1038/nrmicro1794. PubMed DOI

Zarrouk K., Piret J., Boivin G. Herpesvirus DNA polymerases: Structures, functions and inhibitors. Virus Res. 2017;234:177–192. doi: 10.1016/j.virusres.2017.01.019. PubMed DOI

Sauerbrei A., Bohn-Wippert K., Kaspar M., Krumbholz A., Karrasch M., Zell R. Database on natural polymorphisms and resistance-related non-synonymous mutations in thymidine kinase and DNA polymerase genes of herpes simplex virus types 1 and 2. J. Antimicrob. Chemother. 2016;71:6–16. doi: 10.1093/jac/dkv285. PubMed DOI

Knopf K.W., Kaufman E.R., Crumpacker C. Physical mapping of drug resistance mutations defines an active center of the herpes simplex virus DNA polymerase enzyme. J. Virol. 1981;39:746–757. PubMed PMC

Coen D.M., Schaffer P.A. Antiherpesvirus drugs: A promising spectrum of new drugs and drug targets. Nat. Rev. Drug Discov. 2003;2:278–288. doi: 10.1038/nrd1065. PubMed DOI

Morfin F., Thouvenot D. Herpes simplex virus resistance to antiviral drugs. J. Clin. Virol. 2003;26:29–37. doi: 10.1016/S1386-6532(02)00263-9. PubMed DOI

Styczynski J., Reusser P., Einsele H., de la Camara R., Cordonnier C., Ward K.N., Ljungman P., Engelhard D. Management of HSV, VZV and EBV infections in patients with hematological malignancies and after SCT: Guidelines from the Second European Conference on Infections in Leukemia. Bone Marrow Transplant. 2009;43:757–770. doi: 10.1038/bmt.2008.386. PubMed DOI

Shibata S. Der Stoffwechsel Sekundärer Pflanzenstoffe/The Metabolism of Secondary Plant Products. Springer; Berlin/Heidelberg, Germany: 1958. Especial compounds of lichens; pp. 560–623.

Hassan S.T.S., Šudomová M., Berchová-Bímová K., Gowrishankar S., Rengasamy K.R.R. Antimycobacterial, Enzyme Inhibition, and Molecular Interaction Studies of Psoromic Acid in Mycobacterium tuberculosis: Efficacy and Safety Investigations. J. Clin. Med. 2018;7:226. doi: 10.3390/jcm7080226. PubMed DOI PMC

Vartia K.O. The Lichens. Academic Press, Inc.; New York, NY, USA: 1973. Antibiotics in lichens; pp. 547–561.

Sweidan A., Chollet-Krugler M., Sauvager A., Van de Weghe P., Chokr A., Bonnaure-Mallet M., Tomasi S., Bousarghin L. Antibacterial activities of natural lichen compounds against Streptococcus gordonii and Porphyromonas gingivalis. Fitoterapia. 2017;121:164–169. doi: 10.1016/j.fitote.2017.07.011. PubMed DOI

Emsen B., Aslan A., Togar B., Turkez H. In vitro antitumor activities of the lichen compounds olivetoric, physodic and psoromic acid in rat neuron and glioblastoma cells. Pharm. Biol. 2016;54:1748–1762. doi: 10.3109/13880209.2015.1126620. PubMed DOI

Da Rosa Guterres Z., Honda N.K., Coelho R.G., Alcantara G.B., Micheletti A.C. Antigenotoxicity of depsidones isolated from Brazilian lichens. Orbital. Electron. J. Chem. 2017;9:50–54. doi: 10.17807/orbital.v9i1.897. DOI

Brandão L.F.G., Alcantara G.B., Matos M.D.F.C., Bogo D., dos Santos Freitas D., Oyama N.M., Honda N.K. Cytotoxic evaluation of phenolic compounds from lichens against melanoma cells. Chem. Pharm. Bull. 2013;61:176–183. PubMed

Behera B.C., Mahadik N., Morey M. Antioxidative and cardiovascular-protective activities of metabolite usnic acid and psoromic acid produced by lichen species Usnea complanata under submerged fermentation. Pharm. Biol. 2012;50:968–979. doi: 10.3109/13880209.2012.654396. PubMed DOI

Deraeve C.L., Guo Z., Bon R.S., Blankenfeldt W., DiLucrezia R., Wolf A., Menninger S., Stigter E.A., Wetzel S., Choidas A. Psoromic acid is a selective and covalent rab-prenylation inhibitor targeting autoinhibited rabggtase. J. Am. Chem. Soc. 2012;134:7384–7391. doi: 10.1021/ja211305j. PubMed DOI

Reusser P. Herpesvirus resistance to antiviral drugs: A review of the mechanisms, clinical importance and therapeutic options. J. Hosp. Infect. 1996;33:235–248. doi: 10.1016/S0195-6701(96)90010-9. PubMed DOI

Piret J., Boivin G. Resistance of herpes simplex viruses to nucleoside analogues: Mechanisms, prevalence, and management. Antimicrob. Agents Chemother. 2011;55:459–472. doi: 10.1128/AAC.00615-10. PubMed DOI PMC

Cao S., Gan Y., Dong X., Lu Z. Herpes simplex virus type 2 and the risk of cervical cancer: A meta-analysis of observational studies. Arch. Gynecol. Obstet. 2014;290:1059–1066. doi: 10.1007/s00404-014-3365-7. PubMed DOI

Kitazato K., Wang Y., Kobayashi N. Viral infectious disease and natural products with antiviral activity. Drug Discov. Ther. 2007;1:14–22. PubMed

Lawler J.L., Coen D.M. HSV-1 DNA polymerase 3′-5′ exonuclease-deficient mutant D368A exhibits severely reduced viral DNA synthesis and polymerase expression. J. Gen. Virol. 2018;99:1432–1437. doi: 10.1099/jgv.0.001138. PubMed DOI PMC

Zhang J., Wang S., Wang K., Zheng C. Herpes simplex virus 1 DNA polymerase processivity factor UL42 inhibits TNF-α-induced NF-κB activation by interacting with p65/RelA and p50/NF-κB1. Med. Microbiol. Immunol. 2013;202:313–325. doi: 10.1007/s00430-013-0295-0. PubMed DOI

Wathen M.W. Non-nucleoside inhibitors of herpesviruses. Rev. Med. Virol. 2002;12:167–178. doi: 10.1002/rmv.354. PubMed DOI

Eizuru Y. Development of new antivirals for herpesviruses. Antivir. Chem. Chemother. 2003;14:299–308. doi: 10.1177/095632020301400602. PubMed DOI

McClain L., Zhi Y., Cheng H., Ghosh A., Piazza P., Yee M.B., Kumar S., Milosevic J., Bloom D.C., Arav-Boger R., et al. Broad-spectrum non-nucleoside inhibitors of human herpesviruses. Antivir. Res. 2015;121:16–23. doi: 10.1016/j.antiviral.2015.06.005. PubMed DOI PMC

Terry B.J., Liu W.C., Cianci C.W., Proszynski E., Fernandes P., Bush K., Meyers E. Inhibition of herpes simplex virus type 1 DNA polymerase by the natural product oosporein. J. Antibiot. 1992;45:286–288. doi: 10.7164/antibiotics.45.286. PubMed DOI

Mao J.C., Robishaw E.E., Overby L.R. Inhibition of DNA polymerase from herpes simplex virus-infected wi-38 cells by phosphonoacetic Acid. J. Virol. 1975;15:1281–1283. PubMed PMC

Reardon J.E. Herpes simplex virus type 1 DNA polymerase. Mechanism-based affinity chromatography. J. Biol. Chem. 1990;265:7112–7115. PubMed

Liu S., Knafels J.D., Chang J.S., Waszak G.A., Baldwin E.T., Deibel M.R., Jr., Thomsen D.R., Homa F.L., Wells P.A., Tory M.C., et al. Crystal structure of the herpes simplex virus 1 DNA polymerase. J. Biol. Chem. 2006;281:18193–18200. doi: 10.1074/jbc.M602414200. PubMed DOI

Babe L.M., Craik C.S. Viral proteases: Evolution of diverse structural motifs to optimize function. Cell. 1997;91:427–430. doi: 10.1016/S0092-8674(00)80426-2. PubMed DOI

Mello J.F., Botelho N.C., Souza A.M., Oliveira R., Brito M.A., Abrahim-Vieira Bde A., Sodero A.C., Castro H.C., Cabral L.M., Miceli L.A., et al. Computational Studies of Benzoxazinone Derivatives as Antiviral Agents against Herpes Virus Type 1 Protease. Molecules. 2015;20:10689–10704. doi: 10.3390/molecules200610689. PubMed DOI PMC

Waxman L., Darke P.L. The herpesvirus proteases as targets for antiviral chemotherapy. Antivir. Chem. Chemother. 2000;11:1–22. doi: 10.1177/095632020001100101. PubMed DOI

Hoog S.S., Smith W.W., Qiu X., Janson C.A., Hellmig B., McQueney M.S., O’Donnell K., O’Shannessy D., DiLella A.G., Debouck C., et al. Active site cavity of herpesvirus proteases revealed by the crystal structure of herpes simplex virus protease/inhibitor complex. Biochemistry. 1997;36:14023–14029. doi: 10.1021/bi9712697. PubMed DOI

Hassan S.T.S., Berchová-Bímová K., Šudomová M., Malaník M., Šmejkal K., Rengasamy K.R.R. In Vitro Study of Multi-Therapeutic Properties of Thymus bovei Benth. Essential Oil and Its Main Component for Promoting Their Use in Clinical Practice. J. Clin. Med. 2018;7:283. doi: 10.3390/jcm7090283. PubMed DOI PMC

Hassan S.T.S., Berchová-Bímová K., Petráš J., Hassan K.T.S. Cucurbitacin B interacts synergistically with antibiotics against Staphylococcus aureus clinical isolates and exhibits antiviral activity against HSV-1. S. Afr. J. Bot. 2017;108:90–94. doi: 10.1016/j.sajb.2016.10.001. DOI

Hassan S.T.S., Švajdlenka E., Berchová-Bímová K. Hibiscus sabdariffa L. and its bioactive constituents exhibit antiviral activity against HSV-2 and anti-enzymatic properties against urease by an ESI-MS based assay. Molecules. 2017;22:722. doi: 10.3390/molecules22050722. PubMed DOI PMC

Brezáni V., Leláková V., Hassan S.T.S., Berchová-Bímová K., Nový P., Klouček P., Maršík P., Dall’Acqua S., Hošek J., Šmejkal K. Anti-Infectivity against Herpes Simplex Virus and Selected Microbes and Anti-Inflammatory Activities of Compounds Isolated from Eucalyptus globulus Labill. Viruses. 2018;10:360. doi: 10.3390/v10070360. PubMed DOI PMC

Knopf K.W. Properties of herpes simplex virus DNA polymerase and characterization of its associated exonuclease activity. Eur. J. Biochem. 1979;98:231–244. doi: 10.1111/j.1432-1033.1979.tb13181.x. PubMed DOI

Schnute M.E., Anderson D.J., Brideau R.J., Ciske F.L., Collier S.A., Cudahy M.M., Eggen M., Genin M.J., Hopkins T.A., Judge T.M., et al. 2-Aryl-2-hydroxyethylamine substituted 4-oxo-4,7-dihydrothieno [2,3-b]pyridines as broad-spectrum inhibitors of human herpesvirus polymerases. Bioorg. Med. Chem. Lett. 2007;17:3349–3353. doi: 10.1016/j.bmcl.2007.03.102. PubMed DOI

Nishiyama Y., Maeno K., Yoshida S. Correlation of increased nuclease activity with enhanced virus reactivation. Exp. Cell Res. 1982;138:485–489. doi: 10.1016/0014-4827(82)90205-1. PubMed DOI

Cheng Y., Prusoff W.H. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem. Pharmacol. 1973;22:3099–3108. PubMed

Hassan S.T.S., Švajdlenka E. Biological evaluation and molecular docking of protocatechuic acid from Hibiscus sabdariffa L. as a potent urease inhibitor by an ESI-MS based method. Molecules. 2017;22:1696. doi: 10.3390/molecules22101696. PubMed DOI PMC

Dassault Systèmes BIOVIA . Discovery Studio Modeling Environment, Release 2017. Dassault Systèmes; San Diego, CA, USA: 2017.

Flavonoids with Anti-Herpes Simplex Virus Properties: Deciphering Their Mechanisms in Disrupting the Viral Life Cycle

Insights into Antiviral Properties and Molecular Mechanisms of Non-Flavonoid Polyphenols against Human Herpesviruses

Flavonoids Target Human Herpesviruses That Infect the Nervous System: Mechanisms of Action and Therapeutic Insights

Berberine in Human Oncogenic Herpesvirus Infections and Their Linked Cancers

Nutraceutical Curcumin with Promising Protection against Herpesvirus Infections and Their Associated Inflammation: Mechanisms and Pathways

Brassicasterol with Dual Anti-Infective Properties against HSV-1 and Mycobacterium tuberculosis, and Cardiovascular Protective Effect: Nonclinical In Vitro and In Silico Assessments

Shedding Light on the Effect of Natural Anti-Herpesvirus Alkaloids on SARS-CoV-2: A Treatment Option for COVID-19

Natural Products-Derived Chemicals: Breaking Barriers to Novel Anti-HSV Drug Development