Coronaviruses are large, often spherical, enveloped, single-stranded positive-sense RNA viruses, ranging in size from 80-220 nm. Their genomes and protein structures are highly conserved. Three coronaviruses have emerged over the last 20 years as serious human pathogens: SARS-CoV was identified as the causative agent in an outbreak in 2002-2003, Middle East respiratory syndrome (MERS) CoV emerged in 2012 and the novel coronavirus SARS-CoV-2 emerged in 2019-2020. SARS-CoV-2 is the virus responsible for the infectious disease termed COVID-19 (WHO Technical Guidance 2020).

SARS-CoV-2 causes fewer fatalities than either of its predecessors MERS-CoV and SARS-CoV, but it is far more transmissible [17].

* Key recommended reading is highlighted with an asterisk

* Alexander SPH, Armstrong JF, Davenport AP, Davies JA, Faccenda E, Harding SD, Levi-Schaffer F, Maguire JJ, Pawson AJ, Southan C et al.. (2020) A rational roadmap for SARS-CoV-2/COVID-19 pharmacotherapeutic research and development: IUPHAR Review 29. Br J Pharmacol, 177 (21): 4942-4966. [PMID:32358833]

Cannalire R, Cerchia C, Beccari AR, Di Leva FS, Summa V. (2022) Targeting SARS-CoV-2 Proteases and Polymerase for COVID-19 Treatment: State of the Art and Future Opportunities. J Med Chem, 65 (4): 2716-2746. [PMID:33186044]

Chia CSB, Xu W, Shuyi Ng P. (2022) A Patent Review on SARS Coronavirus Main Protease (3CL^pro ) Inhibitors. ChemMedChem, 17 (1): e202100576. [PMID:34651447]

Cui J, Li F, Shi ZL. (2019) Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol, 17 (3): 181-192. [PMID:30531947]

de Wit E, van Doremalen N, Falzarano D, Munster VJ. (2016) SARS and MERS: recent insights into emerging coronaviruses. Nat Rev Microbiol, 14 (8): 523-34. [PMID:27344959]

Desforges M, Le Coupanec A, Dubeau P, Bourgouin A, Lajoie L, Dubé M, Talbot PJ. (2019) Human Coronaviruses and Other Respiratory Viruses: Underestimated Opportunistic Pathogens of the Central Nervous System?. Viruses, 12 (1). [PMID:31861926]

Fehr AR, Perlman S. (2015) Coronaviruses: an overview of their replication and pathogenesis. Methods Mol Biol, 1282: 1-23. [PMID:25720466]

* Kronenberger T, Laufer SA, Pillaiyar T. (2023) COVID-19 therapeutics: Small-molecule drug development targeting SARS-CoV-2 main protease. Drug Discov Today, 28 (6): 103579. [PMID:37028502]

* Li G, Hilgenfeld R, Whitley R, De Clercq E. (2023) Therapeutic strategies for COVID-19: progress and lessons learned. Nat Rev Drug Discov, 22 (6): 449-475. [PMID:37076602]

Masters PS. (2006) The molecular biology of coronaviruses. Adv Virus Res, 66: 193-292. [PMID:16877062]

* Pang X, Xu W, Liu Y, Li H, Chen L. (2023) The research progress of SARS-CoV-2 main protease inhibitors from 2020 to 2022. Eur J Med Chem, 257: 115491. [PMID:37244162]

* Pozzi C, Vanet A, Francesconi V, Tagliazucchi L, Tassone G, Venturelli A, Spyrakis F, Mazzorana M, Costi MP, Tonelli M. (2023) Antitarget, Anti-SARS-CoV-2 Leads, Drugs, and the Drug Discovery-Genetics Alliance Perspective. J Med Chem, 66 (6): 3664-3702. [PMID:36857133]

Song Z, Xu Y, Bao L, Zhang L, Yu P, Qu Y, Zhu H, Zhao W, Han Y, Qin C. (2019) From SARS to MERS, Thrusting Coronaviruses into the Spotlight. Viruses, 11 (1). [PMID:30646565]

* von Delft A, Hall MD, Kwong AD, Purcell LA, Saikatendu KS, Schmitz U, Tallarico JA, Lee AA. (2023) Accelerating antiviral drug discovery: lessons from COVID-19. Nat Rev Drug Discov, 22 (7): 585-603. [PMID:37173515]

* Yang T, Wang SC, Ye L, Maimaitiyiming Y, Naranmandura H. (2023) Targeting viral proteins for restraining SARS-CoV-2: focusing lens on viral proteins beyond spike for discovering new drug targets. Expert Opin Drug Discov, 18 (3): 247-268. [PMID:36723288]

Zhang K, Zheludev IN, Hagey RJ, Haslecker R, Hou YJ, Kretsch R, Pintilie GD, Rangan R, Kladwang W, Li S et al.. (2021) Cryo-EM and antisense targeting of the 28-kDa frameshift stimulation element from the SARS-CoV-2 RNA genome. Nat Struct Mol Biol, 28 (9): 747-754. [PMID:34426697]

Zumla A, Chan JF, Azhar EI, Hui DS, Yuen KY. (2016) Coronaviruses - drug discovery and therapeutic options. Nat Rev Drug Discov, 15 (5): 327-47. [PMID:26868298]

1. Cottam EM, Whelband MC, Wileman T. (2014) Coronavirus NSP6 restricts autophagosome expansion. Autophagy, 10 (8): 1426-41. [PMID:24991833]

2. Dai W, Zhang B, Jiang XM, Su H, Li J, Zhao Y, Xie X, Jin Z, Peng J, Liu F et al.. (2020) Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease. Science, 368 (6497): 1331-1335. [PMID:32321856]

3. Fan H, Ooi A, Tan YW, Wang S, Fang S, Liu DX, Lescar J. (2005) The nucleocapsid protein of coronavirus infectious bronchitis virus: crystal structure of its N-terminal domain and multimerization properties. Structure, 13 (12): 1859-68. [PMID:16338414]

4. Freitas BT, Durie IA, Murray J, Longo JE, Miller HC, Crich D, Hogan RJ, Tripp RA, Pegan SD. (2020) Characterization and Noncovalent Inhibition of the Deubiquitinase and deISGylase Activity of SARS-CoV-2 Papain-Like Protease. ACS Infect Dis, 6 (8): 2099-2109. [PMID:32428392]

5. Godoy AS, Nakamura AM, Douangamath A, Song Y, Noske GD, Gawriljuk VO, Fernandes RS, Pereira HDM, Oliveira KIZ, Fearon D et al.. (2023) Allosteric regulation and crystallographic fragment screening of SARS-CoV-2 NSP15 endoribonuclease. Nucleic Acids Res, 51 (10): 5255-5270. DOI: 10.1101/2022.09.26.509485 [PMID:37115000]

6. Gordon CJ, Tchesnokov EP, Woolner E, Perry JK, Feng JY, Porter DP, Götte M. (2020) Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency. J Biol Chem, 295 (20): 6785-6797. [PMID:32284326]

7. Hansen J, Baum A, Pascal KE, Russo V, Giordano S, Wloga E, Fulton BO, Yan Y, Koon K, Patel K et al.. (2020) Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail. Science, 369 (6506): 1010-1014. [PMID:32540901]

8. Harcourt BH, Jukneliene D, Kanjanahaluethai A, Bechill J, Severson KM, Smith CM, Rota PA, Baker SC. (2004) Identification of severe acute respiratory syndrome coronavirus replicase products and characterization of papain-like protease activity. J Virol, 78 (24): 13600-12. [PMID:15564471]

9. Hilgenfeld R. (2014) From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design. FEBS J, 281 (18): 4085-96. [PMID:25039866]

10. Imbert I, Guillemot JC, Bourhis JM, Bussetta C, Coutard B, Egloff MP, Ferron F, Gorbalenya AE, Canard B. (2006) A second, non-canonical RNA-dependent RNA polymerase in SARS coronavirus. EMBO J, 25 (20): 4933-42. [PMID:17024178]

11. Kim C, Ryu DK, Lee J, Kim YI, Seo JM, Kim YG, Jeong JH, Kim M, Kim JI, Kim P et al.. (2021) A therapeutic neutralizing antibody targeting receptor binding domain of SARS-CoV-2 spike protein. Nat Commun, 12 (1): 288. [PMID:33436577]

12. Kim Y, Wower J, Maltseva N, Chang C, Jedrzejczak R, Wilamowski M, Kang S, Nicolaescu V, Randall G, Michalska K et al.. (2021) Tipiracil binds to uridine site and inhibits Nsp15 endoribonuclease NendoU from SARS-CoV-2. Commun Biol, 4 (1): 193. [PMID:33564093]

13. La Monica G, Bono A, Lauria A, Martorana A. (2022) Targeting SARS-CoV-2 Main Protease for Treatment of COVID-19: Covalent Inhibitors Structure-Activity Relationship Insights and Evolution Perspectives. J Med Chem, [Epub ahead of print]. DOI: 10.1021/acs.jmedchem.2c01005 [PMID:36169610]

14. Osipiuk J, Azizi SA, Dvorkin S, Endres M, Jedrzejczak R, Jones KA, Kang S, Kathayat RS, Kim Y, Lisnyak VG et al.. (2021) Structure of papain-like protease from SARS-CoV-2 and its complexes with non-covalent inhibitors. Nat Commun, 12 (1): 743. [PMID:33531496]

15. Owen DR, Allerton CMN, Anderson AS, Aschenbrenner L, Avery M, Berritt S, Boras B, Cardin RD, Carlo A, Coffman KJ et al.. (2021) An oral SARS-CoV-2 M^pro inhibitor clinical candidate for the treatment of COVID-19. Science, 374 (6575): 1586-1593. [PMID:34726479]

16. Pervushin K, Tan E, Parthasarathy K, Lin X, Jiang FL, Yu D, Vararattanavech A, Soong TW, Liu DX, Torres J. (2009) Structure and inhibition of the SARS coronavirus envelope protein ion channel. PLoS Pathog, 5 (7): e1000511. [PMID:19593379]

17. Petersen E, Koopmans M, Go U, Hamer DH, Petrosillo N, Castelli F, Storgaard M, Al Khalili S, Simonsen L. (2020) Comparing SARS-CoV-2 with SARS-CoV and influenza pandemics. Lancet Infect Dis, 20 (9): e238-e244. [PMID:32628905]

18. Pfefferle S, Krähling V, Ditt V, Grywna K, Mühlberger E, Drosten C. (2009) Reverse genetic characterization of the natural genomic deletion in SARS-Coronavirus strain Frankfurt-1 open reading frame 7b reveals an attenuating function of the 7b protein in-vitro and in-vivo. Virol J, 6: 131. [PMID:19698190]

19. Pillaiyar T, Manickam M, Namasivayam V, Hayashi Y, Jung SH. (2016) An Overview of Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy. J Med Chem, 59 (14): 6595-628. [PMID:26878082]

20. Ruch TR, Machamer CE. (2012) The coronavirus E protein: assembly and beyond. Viruses, 4 (3): 363-82. [PMID:22590676]

21. Shen Z, Ratia K, Cooper L, Kong D, Lee H, Kwon Y, Li Y, Alqarni S, Huang F, Dubrovskyi O et al.. (2022) Design of SARS-CoV-2 PLpro Inhibitors for COVID-19 Antiviral Therapy Leveraging Binding Cooperativity. J Med Chem, 65 (4): 2940-2955. [PMID:34665619]

22. Shi CS, Qi HY, Boularan C, Huang NN, Abu-Asab M, Shelhamer JH, Kehrl JH. (2014) SARS-coronavirus open reading frame-9b suppresses innate immunity by targeting mitochondria and the MAVS/TRAF3/TRAF6 signalosome. J Immunol, 193 (6): 3080-9. [PMID:25135833]

23. Shin D, Mukherjee R, Grewe D, Bojkova D, Baek K, Bhattacharya A, Schulz L, Widera M, Mehdipour AR, Tascher G et al.. (2020) Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity. Nature, 587 (7835): 657-662. [PMID:32726803]

24. Surya W, Li Y, Verdià-Bàguena C, Aguilella VM, Torres J. (2015) MERS coronavirus envelope protein has a single transmembrane domain that forms pentameric ion channels. Virus Res, 201: 61-6. [PMID:25733052]

25. Tan YJ, Fielding BC, Goh PY, Shen S, Tan TH, Lim SG, Hong W. (2004) Overexpression of 7a, a protein specifically encoded by the severe acute respiratory syndrome coronavirus, induces apoptosis via a caspase-dependent pathway. J Virol, 78 (24): 14043-7. [PMID:15564512]

26. te Velthuis AJ, van den Worm SH, Snijder EJ. (2012) The SARS-coronavirus nsp7+nsp8 complex is a unique multimeric RNA polymerase capable of both de novo initiation and primer extension. Nucleic Acids Res, 40 (4): 1737-47. [PMID:22039154]

27. Wang Y, Anirudhan V, Du R, Cui Q, Rong L. (2021) RNA-dependent RNA polymerase of SARS-CoV-2 as a therapeutic target. J Med Virol, 93 (1): 300-310. [PMID:32633831]

28. Wilson L, McKinlay C, Gage P, Ewart G. (2004) SARS coronavirus E protein forms cation-selective ion channels. Virology, 330 (1): 322-31. [PMID:15527857]

29. Xia S, Liu M, Wang C, Xu W, Lan Q, Feng S, Qi F, Bao L, Du L, Liu S et al.. (2020) Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion. Cell Res, 30 (4): 343-355. [PMID:32231345]

30. Xu K, Zheng BJ, Zeng R, Lu W, Lin YP, Xue L, Li L, Yang LL, Xu C, Dai J et al.. (2009) Severe acute respiratory syndrome coronavirus accessory protein 9b is a virion-associated protein. Virology, 388 (2): 279-85. [PMID:19394665]

31. Zhang R, Wang K, Lv W, Yu W, Xie S, Xu K, Schwarz W, Xiong S, Sun B. (2014) The ORF4a protein of human coronavirus 229E functions as a viroporin that regulates viral production. Biochim Biophys Acta, 1838 (4): 1088-95. [PMID:23906728]

32. Zhang Z, Nomura N, Muramoto Y, Ekimoto T, Uemura T, Liu K, Yui M, Kono N, Aoki J, Ikeguchi M et al.. (2022) Structure of SARS-CoV-2 membrane protein essential for virus assembly. Nat Commun, 13 (1): 4399. [PMID:35931673]

33. Zhu W, Chen CZ, Gorshkov K, Xu M, Lo DC, Zheng W. (2020) RNA-Dependent RNA Polymerase as a Target for COVID-19 Drug Discovery. SLAS Discov, 25 (10): 1141-1151. [PMID:32660307]

Subcommittee members: Stephen P.H. Alexander Associate Professor in Molecular Pharmacology Life Sciences E Floor University of Nottingham Medical School Nottingham NG7 2UH UK Jonathan K. Ball Room Microbiology, A Floor West Block QMC Queen's Medical Centre Nottingham NG7 2UH UK Theocharis Tsoleridis Room West Block, A Floor, Room 16 Queen's Medical Centre Nottingham NG7 2UH UK