SARS-CoV-2 has caused an extensive pandemic of COVID-19 all around the world. Key viral enzymes are suitable molecular targets for the development of new antivirals against SARS-CoV-2 which could represent potential treatments of the corresponding disease. With respect to its essential role in the replication of viral RNA, RNA-dependent RNA polymerase (RdRp) is one of the prime targets. HeE1-2Tyr and related derivatives were originally discovered as inhibitors of the RdRp of flaviviruses. Here, we present that these pyridobenzothiazole derivatives also significantly inhibit SARS-CoV-2 RdRp, as demonstrated using both polymerase- and cell-based antiviral assays.

Department of Pharmacology and Pharmacy Faculty of Veterinary Medicine University of Veterinary Sciences Brno Palackého tř 1946 1 612 42 Brno Czech Republic

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Flemingovo náměstí 542 2 160 00 Praha Czech Republic

Institute of Parasitology Biology Centre of the Czech Academy of Sciences Branišovská 1160 31 370 05 České Budějovice Czech Republic

Veterinary Research Institute Emerging Viral Diseases Hudcova 296 70 621 00 Brno Czech Republic

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Cui J., Li F., Shi Z.L. Origin and evolution of pathogenic coronaviruses. Nat. Rev. Microbiol. 2019;17:181–192. doi: 10.1038/s41579-018-0118-9. PubMed DOI PMC

De Wit J.J., Cook J.K.A. Spotlight on avian coronaviruses. Avian Pathol. 2020;49:313–316. doi: 10.1080/03079457.2020.1761010. PubMed DOI

Monchatre-Leroy E., Boue F., Boucher J.M., Renault C., Moutou F., Gouilh M.A., Umhang G. Identification of Alpha and Beta Coronavirus in Wildlife Species in France: Bats, Rodents, Rabbits, and Hedgehogs. Viruses. 2017;9:364. doi: 10.3390/v9120364. PubMed DOI PMC

Chen Y., Liu Q.Y., Guo D.Y. Emerging coronaviruses: Genome structure, replication, and pathogenesis. J. Med. Virol. 2020;92:418–423. doi: 10.1002/jmv.25681. PubMed DOI PMC

De Wit E., Van Doremalen N., Falzarano D., Munster V.J. SARS and MERS: Recent insights into emerging coronaviruses. Nat. Rev. Microbiol. 2016;14:523–534. doi: 10.1038/nrmicro.2016.81. PubMed DOI PMC

Zumla A., Chan J.F.W., Azhar E.I., Hui D.S.C., Yuen K.-Y. Coronaviruses—Drug discovery and therapeutic options. Nat. Rev. Drug Discov. 2016;15:327–347. doi: 10.1038/nrd.2015.37. PubMed DOI PMC

Gorbalenya A.E., Baker S.C., Baric R.S., De Groot R.J., Drosten C., Gulyaeva A.A., Haagmans B.L., Lauber C., Leontovich A.M., Neuman B.W., et al. The species Severe acute respiratory syndrome-related coronavirus: Classifying 2019-nCoV and naming it SARS-CoV-2. Nat. Microbiol. 2020;5:536–544. doi: 10.1038/s41564-020-0695-z. PubMed DOI PMC

Lu L., Zhong W.Y., Bian Z.W., Li Z.M., Zhang K., Liang B.X., Zhong Y.Z., Hu M.J., Lin L., Liu J., et al. A comparison of mortality-related risk factors of COVID-19, SARS, and MERS: A systematic review and meta-analysis. J. Infect. 2020;81:E18–E25. doi: 10.1016/j.jinf.2020.07.002. PubMed DOI PMC

Finelli L., Gupta V., Petigara T., Yu K., Bauer K.A., Puzniak L.A. Mortality Among US Patients Hospitalized With SARS-CoV-2 Infection in 2020. JAMA Netw. Open. 2021;4:e216556. doi: 10.1001/jamanetworkopen.2021.6556. PubMed DOI PMC

Tumban E. Lead SARS-CoV-2 Candidate Vaccines: Expectations from Phase III Trials and Recommendations Post-Vaccine Approval. Viruses. 2021;13:54. doi: 10.3390/v13010054. PubMed DOI PMC

Wu D., Koganti R., Lambe U.P., Yadavalli T., Nandi S.S., Shukla D. Vaccines and Therapies in Development for SARS-CoV-2 Infections. J. Clin. Med. 2020;9:1885. doi: 10.3390/jcm9061885. PubMed DOI PMC

Pedersen O.S., Pedersen E.B. Non-nucleoside reverse transcriptase inhibitors: The NNRTI boom. Antivir. Chem. Chemother. 1999;10:285–314. doi: 10.1177/095632029901000601. PubMed DOI

Dayal V., Kumar A., Jha S.K., Sharan A., Kumar U., Shahi S.K. Viral Hepatitis ( plus Antiviral Therapy) Combination therapy of lamivudine and adefovir in patients of HBeAg positive chronic hepatitis B. J. Gastroenterol. Hepatol. 2013;28:419.

Das D., Pandya M. Recent Advancement of Direct-acting Antiviral Agents (DAAs) in Hepatitis C Therapy. Mini-Rev. Med. Chem. 2018;18:584–596. doi: 10.2174/1389557517666170913111930. PubMed DOI

Vicenti I., Zazzi M., Saladini F. SARS-CoV-2 RNA-dependent RNA polymerase as a therapeutic target for COVID-19. Expert Opin. Ther. Pat. 2021;31:325–337. doi: 10.1080/13543776.2021.1880568. PubMed DOI PMC

Perry J.K., Appleby T.C., Bilello J.P., Feng J.Y., Schmitz U., Campbell E.A. An atomistic model of the coronavirus replication-transcription complex as a hexamer assembled around nsp15. bioRxiv. 2021 doi: 10.1101/2021.06.08.447516. PubMed DOI PMC

Hillen H.S., Kokic G., Farnung L., Dienemann C., Tegunov D., Cramer P. Structure of replicating SARS-CoV-2 polymerase. Nature. 2020;584:154–156. doi: 10.1038/s41586-020-2368-8. PubMed DOI

Pruijssers A.J., George A.S., Schafer A., Leist S.R., Gralinksi L.E., Dinnon K.H., Yount B.L., Agostini M.L., Stevens L.J., Chappell J.D., et al. Remdesivir Inhibits SARS-CoV-2 in Human Lung Cells and Chimeric SARS-CoV Expressing the SARS-CoV-2 RNA Polymerase in Mice. Cell Rep. 2020;32:107940. doi: 10.1016/j.celrep.2020.107940. PubMed DOI PMC

Yin W.C., Luan X.D., Li Z.H., Zhou Z.W., Wang Q.X., Gao M.Q., Wang X.X., Zhou F.L., Shi J.J., You E.R., et al. Structural basis for inhibition of the SARS-CoV-2 RNA polymerase by suramin. Nat. Struct. Mol. Biol. 2021;28:319–325. doi: 10.1038/s41594-021-00570-0. PubMed DOI

Li Q., Yi D., Lei X., Zhao J., Zhang Y., Cui X., Xiao X., Jiao T., Dong X., Zhao X., et al. Corilagin inhibits SARS-CoV-2 replication by targeting viral RNA-dependent RNA polymerase. Acta Pharm. Sin. B. 2021;11:1555–1567. doi: 10.1016/j.apsb.2021.02.011. PubMed DOI PMC

Jin Y.H., Min J.S., Jeon S., Lee J., Kim S., Park T., Park D., Jang M.S., Park C.M., Song J.H., et al. Lycorine, a non-nucleoside RNA dependent RNA polymerase inhibitor, as potential treatment for emerging coronavirus infections. Phytomedicine. 2021;86:153440. doi: 10.1016/j.phymed.2020.153440. PubMed DOI PMC

Agrawal N., Goyal A. Potential Candidates against COVID-19 Targeting RNA-Dependent RNA Polymerase: A Comprehensive Review. Curr. Pharm. Biotechnol. 2021 doi: 10.2174/1389201022666210421102513. PubMed DOI

Tarantino D., Cannalire R., Mastrangelo E., Croci R., Querat G., Barreca M.L., Bolognesi M., Manfroni G., Cecchetti V., Milani M. Targeting flavivirus RNA dependent RNA polymerase through a pyridobenzothiazole inhibitor. Antivir. Res. 2016;134:226–235. doi: 10.1016/j.antiviral.2016.09.007. PubMed DOI

Cannalire R., Tarantino D., Piorkowski G., Carletti T., Massari S., Felicetti T., Barreca M.L., Sabatini S., Tabarrini O., Marcello A., et al. Broad spectrum anti-flavivirus pyridobenzothiazolones leading to less infective virions. Antivir. Res. 2019;167:6–12. doi: 10.1016/j.antiviral.2019.03.004. PubMed DOI

Cannalire R., Chan K.W.K., Burali M.S., Gwee C.P., Wang S., Astolfi A., Massari S., Sabatini S., Tabarrini O., Mastrangelo E., et al. Pyridobenzothiazolones Exert Potent Anti-Dengue Activity by Hampering Multiple Functions of NS5 Polymerase. ACS Med. Chem. Lett. 2020;11:773–782. doi: 10.1021/acsmedchemlett.9b00619. PubMed DOI PMC

Felicetti T., Burali M.S., Gwee C.P., Chan K.W.K., Alonso S., Massari S., Sabatini S., Tabarrini O., Barreca M.L., Cecchetti V., et al. Sustainable, three-component, one-pot procedure to obtain active anti-flavivirus agents. Eur. J. Med. Chem. 2021;210:112992. doi: 10.1016/j.ejmech.2020.112992. PubMed DOI

Konkolova E., Dejmek M., Hrebabecky H., Sala M., Boserle J., Nencka R., Boura E. Remdesivir triphosphate can efficiently inhibit the RNA-dependent RNA polymerase from various flaviviruses. Antivir. Res. 2020;182:104899. doi: 10.1016/j.antiviral.2020.104899. PubMed DOI PMC

De Madrid A.T., Porterfield J.S. A simple micro-culture method for the study of group B arboviruses. Bull. World Health Organ. 1969;40:113–121. PubMed PMC

Eyer L., Valdes J.J., Gil V.A., Nencka R., Hrebabecky H., Sala M., Salat J., Cerny J., Palus M., De Clercq E., et al. Nucleoside Inhibitors of Tick-Borne Encephalitis Virus. Antimicrob. Agents Chemother. 2015;59:5483–5493. doi: 10.1128/AAC.00807-15. PubMed DOI PMC

Enzymatic synthesis of reactive RNA probes containing squaramate-linked cytidine or adenosine for bioconjugations and cross-linking with lysine-containing peptides and proteins

Novel analogues of a nonnucleoside SARS-CoV-2 RdRp inhibitor as potential antivirotics

A Helquat-like Compound as a Potent Inhibitor of Flaviviral and Coronaviral Polymerases