Coronaviruses (CoVs) can cause highly prevalent diseases in humans and animals. The fatal outbreak of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) highlights the threat posed by this unique virus subfamily. However, no specific drugs have been approved to treat CoV-associated diseases to date. The CoV proteases, which play pivotal roles in viral gene expression and replication through a highly complex cascade involving the proteolytic processing of replicase polyproteins, are attractive targets for drug design. This review summarizes the recent advances in biological and structural studies, together with the development of inhibitors targeting CoV proteases, particularly main proteases (Mpros), which could help develop effective treatments to prevent CoV infection.
Adedeji AO, Sarafianos SG. 2014. Antiviral drugs specific for coronaviruses in preclinical development. Curr Opin Virol, 8: 45–53.
Anand K, Ziebuhr J, Wadhwani P, Mesters JR, Hilgenfeld R. 2003. Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs. Science, 300: 1763–1767.
Baez-Santos YM, Barraza SJ, Wilson MW, Agius MP, Mielech AM, Davis NM, Baker SC, Larsen SD, Mesecar AD. 2014. Xray structural and biological evaluation of a series of potent and highly selective inhibitors of human coronavirus papain-like proteases. J Med Chem, 57: 2393–2412.
Baez-Santos YM, St John SE, Mesecar AD. 2015. The SARScoronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds. Antiviral Res, 115: 21–38.
Chan JF, To KK, Tse H, Jin DY, Yuen KY. 2013. Interspecies transmission and emergence of novel viruses: lessons from bats and birds. Trends Microbiol, 21: 544–555.
Chen LR, Wang YC, Lin YW, Chou SY, Chen SF, Liu LT, Wu YT, Kuo CJ, Chen TS, Juang SH. 2005. Synthesis and evaluation of isatin derivatives as effective SARS coronavirus 3CL protease inhibitors. Bioorg Med Chem Lett, 15: 3058–3062.
Chen X, Chou CY, Chang GG. 2009. Thiopurine analogue inhibitors of severe acute respiratory syndrome-coronavirus papainlike protease, a deubiquitinating and deISGylating enzyme. Antivir Chem Chemother, 19: 151–156.
Chen Y, Savinov SN, Mielech AM, Cao T, Baker SC, Mesecar AD. 2015. X-ray Structural and Functional Studies of the Three Tandemly Linked Domains of Non-structural Protein 3 (nsp3) from Murine Hepatitis Virus Reveal Conserved Functions. J Biol Chem, 290: 25293–25306.
Cho JK, Curtis-Long MJ, Lee KH, Kim DW, Ryu HW, Yuk HJ, Park KH. 2013. Geranylated flavonoids displaying SARS-CoV papain-like protease inhibition from the fruits of Paulownia tomentosa. Bioorg Med Chem, 21: 3051–3057.
Chuck CP, Ke ZH, Chen C, Wan DC, Chow HF, Wong KB. 2014. Profiling of substrate-specificity and rational design of broadspectrum peptidomimetic inhibitors for main proteases of coronaviruses. Hong Kong Med J, 20 Suppl 4: 22–25.
Cornillez-Ty CT, Liao L, Yates JR, Kuhn P, Buchmeier MJ. 2009. Severe acute respiratory syndrome coronavirus nonstructural protein 2 interacts with a host protein complex involved in mitochondrial biogenesis and intracellular signaling. J Virol, 83: 10314–10318.
Dominguez A, Gudiol F, Pumarola T, Salleras L. 2003. Severe acute respiratory syndrome epidemics: the end or a hiatus of the epidemic? Med Clin (Barc), 121: 340–346. (In Spanish)
Drosten C, Gunther S, Preiser W, van der Werf S, Brodt HR, Becker S, Rabenau H, Panning M, Kolesnikova L, Fouchier RA, Berger A, Burguiere AM, Cinatl J, Eickmann M, Escriou N, Grywna K, Kramme S, Manuguerra JC, Muller S, Rickerts V, Sturmer M, Vieth S, Klenk HD, Osterhaus AD, Schmitz H, Doerr HW. 2003. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med, 348: 1967–1976.
Franco-Paredes C, Kuri-Morales P, Alvarez-Lucas C, Palacios-Zavala E, Nava-Frias M, Betancourt-Cravioto M, Santos-Preciado JI, Tapia-Conyer R. 2003. Severe acute respiratory syndrome: a global overview of the epidemic. Salud Publica Mex, 45: 211–220. (In Spanish)
Ge XY, Li JL, Yang XL, Chmura AA, Zhu G, Epstein JH, Mazet JK, Hu B, Zhang W, Peng C, Zhang YJ, Luo CM, Tan B, Wang N, Zhu Y, Crameri G, Zhang SY, Wang LF, Daszak P, Shi ZL. 2013. Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. Nature, 503: 535–538.
Ghosh AK, Takayama J, Aubin Y, Ratia K, Chaudhuri R, Baez Y, Sleeman K, Coughlin M, Nichols DB, Mulhearn DC, Prabhakar BS, Baker SC, Johnson ME, Mesecar AD. 2009. Structurebased design, synthesis, and biological evaluation of a series of novel and reversible inhibitors for the severe acute respiratory syndrome-coronavirus papain-like protease. J Med Chem, 52: 5228–5240.
Ghosh AK, Takayama J, Rao KV, Ratia K, Chaudhuri R, Mulhearn DC, Lee H, Nichols DB, Baliji S, Baker SC, Johnson ME, Mesecar AD. 2010. Severe acute respiratory syndrome coronavirus papain-like novel protease inhibitors: design, synthesis, protein-ligand X-ray structure and biological evaluation. J Med Chem, 53: 4968–4979.
Ghosh AK, Xi K, Grum-Tokars V, Xu X, Ratia K, Fu W, Houser KV, Baker SC, Johnson ME, Mesecar AD. 2007. Structurebased design, synthesis, and biological evaluation of peptidomimetic SARS-CoV 3CLpro inhibitors. Bioorg Med Chem Lett, 17: 5876–5880.
Han YS, Chang GG, Juo CG, Lee HJ, Yeh SH, Hsu JT, Chen X. 2005. Papain-like protease 2 (PLP2) from severe acute respiratory syndrome coronavirus (SARS-CoV): expression, purification, characterization, and inhibition. Biochemistry, 44: 10349–10359.
Ivanov KA, Thiel V, Dobbe JC, van der Meer Y, Snijder EJ, Ziebuhr J. 2004. Multiple enzymatic activities associated with severe acute respiratory syndrome coronavirus helicase. J Virol, 78: 5619–5632.
Kim Y, Shivanna V, Narayanan S, Prior AM, Weerasekara S, Hua DH, Kankanamalage AC, Groutas WC, Chang KO. 2015. Broad-spectrum inhibitors against 3C-like proteases of feline coronaviruses and feline caliciviruses. J Virol, 89: 4942–4950.
Kuiken T, Fouchier RAM, Schutten M, Rimmelzwaan GF, van Amerongen G, van Riel D, Laman JD, de Jong T, van Doornum G, Lim W, Ling AE, Chan PKS, Tam JS, Zambon MC, Gopal R, Drosten C, van der Werf S, Escriou N, Manuguerra J-C, Stöhr K, Peiris JSM, Osterhaus ADME. 2003. Newly discovered coronavirus as the primary cause of severe acute respiratory syndrome. Lancet, 362: 263–270.
Lee H, Lei H, Santarsiero BD, Gatuz JL, Cao S, Rice AJ, Patel K, Szypulinski MZ, Ojeda I, Ghosh AK, Johnson ME. 2015. Inhibitor recognition specificity of MERS-CoV papain-like protease may differ from that of SARS-CoV. ACS Chem Biol, 10: 1456–1465.
Liu W, Zhu HM, Niu GJ, Shi EZ, Chen J, Sun B, Chen WQ, Zhou HG, Yang C. 2014. Synthesis, modification and docking studies of 5-sulfonyl isatin derivatives as SARS-CoV 3C-like protease inhibitors. Bioorg Med Chem, 22: 292–302.
Lu G, Wang Q, Gao GF. 2015. Bat-to-human: spike features determining 'host jump' of coronaviruses SARS-CoV, MERSCoV, and beyond. Trends Microbiol, 23: 468–478.
Mukherjee P, Desai P, Ross L, White EL, Avery MA. 2008. Structure-based virtual screening against SARS-3CL(pro) to identify novel non-peptidic hits. Bioorg Med Chem, 16: 4138–4149.
Mukherjee P, Shah F, Desai P, Avery M. 2011. Inhibitors of SARS-3CLpro: virtual screening, biological evaluation, and molecular dynamics simulation studies. J Chem Inf Model, 51: 1376–1392.
Narayanan K, Huang C, Lokugamage K, Kamitani W, Ikegami T, Tseng CT, et al. 2008. Severe acute respiratory syndrome coronavirus nsp1 suppresses host gene expression, including that of type I interferon, in infected cells. J Virol. 82: 4471–4479.
Ng ML, Tan SH, See EE, Ooi EE, Ling AE. 2003. Early events of SARS coronavirus infection in vero cells. Journal of medical virology. 71: 323–331.
Paasche A, Zipper A, Schafer S, Ziebuhr J, Schirmeister T, Engels B. 2014. Evidence for substrate binding-induced zwitterion formation in the catalytic Cys-His dyad of the SARS-CoV main protease. Biochemistry, 53: 5930–5946.
Park JY, Jeong HJ, Kim JH, Kim YM, Park SJ, Kim D, Park KH, Lee WS, Ryu YB. 2012a. Diarylheptanoids from Alnus japonica inhibit papain-like protease of severe acute respiratory syndrome coronavirus. Biol Pharm Bull, 35: 2036–2042.
Park JY, Kim JH, Kim YM, Jeong HJ, Kim DW, Park KH, Kwon HJ, Park SJ, Lee WS, Ryu YB. 2012b. Tanshinones as selective and slow-binding inhibitors for SARS-CoV cysteine proteases. Bioorg Med Chem, 20: 5928–5935.
Ramajayam R, Tan KP, Liu HG, Liang PH. 2010. Synthesis, docking studies, and evaluation of pyrimidines as inhibitors of SARS-CoV 3CL protease. Bioorg Med Chem Lett, 20: 3569–3572.
Ratia K, Pegan S, Takayama J, Sleeman K, Coughlin M, Baliji S, Chaudhuri R, Fu W, Prabhakar BS, Johnson ME, Baker SC, Ghosh AK, Mesecar AD. 2008. A noncovalent class of papainlike protease/deubiquitinase inhibitors blocks SARS virus replication. Proc Natl Acad Sci U S A, 105: 16119–16124.
Rota PA, Oberste MS, Monroe SS, Nix WA, Campagnoli R, Icenogle JP, Penaranda S, Bankamp B, Maher K, Chen MH, Tong S, Tamin A, Lowe L, Frace M, DeRisi JL, Chen Q, Wang D, Erdman DD, Peret TC, Burns C, Ksiazek TG, Rollin PE, Sanchez A, Liffick S, Holloway B, Limor J, McCaustland K, Olsen-Rasmussen M, Fouchier R, Gunther S, Osterhaus AD, Drosten C, Pallansch MA, Anderson LJ, Bellini WJ. 2003. Characterization of a novel coronavirus associated with severe acute respiratory syndrome. Science, 300: 1394–1399.
Shao YM, Yang WB, Kuo TH, Tsai KC, Lin CH, Yang AS, Liang PH, Wong CH. 2008. Design, synthesis, and evaluation of trifluoromethyl ketones as inhibitors of SARS-CoV 3CL protease. Bioorg Med Chem, 16: 4652–4660.
Shi J, Sivaraman J, Song J. 2008. Mechanism for controlling the dimer-monomer switch and coupling dimerization to catalysis of the severe acute respiratory syndrome coronavirus 3C-like protease. J Virol, 82: 4620–4629.
Shimamoto Y, Hattori Y, Kobayashi K, Teruya K, Sanjoh A, Nakagawa A, Yamashita E, Akaji K. 2015. Fused-ring structure of decahydroisoquinolin as a novel scaffold for SARS 3CL protease inhibitors. Bioorg Med Chem, 23: 876–890.
Snijder EJ, Bredenbeek PJ, Dobbe JC, Thiel V, Ziebuhr J, Poon LL, et al. 2003. Unique and conserved features of genome and proteome of SARS-coronavirus, an early split-off from the coronavirus group 2 lineage. J Mol Biol, 331: 991–1004.
St John SE, Tomar S, Stauffer SR, Mesecar AD. 2015. Targeting zoonotic viruses: Structure-based inhibition of the 3C-like protease from bat coronavirus HKU4—The likely reservoir host to the human coronavirus that causes Middle East Respiratory Syndrome (MERS). Bioorg Med Chem, 23: 6036–6048.
Sun L, Xing Y, Chen X, Zheng Y, Yang Y, Nichols DB, Clementz MA, Banach BS, Li K, Baker SC, Chen Z. 2012. Coronavirus papain-like proteases negatively regulate antiviral innate immune response through disruption of STING-mediated signaling. PLoS One, 7: e30802.
Sutton G, Fry E, Carter L, Sainsbury S, Walter T, Nettleship J, et al. 2004. The nsp9 replicase protein of SARS-coronavirus, structure and functional insights. Structure, 12: 341–353.
te Velthuis AJ, van den Worm SH, Snijder EJ. 2012. The SARScoronavirus nsp7+nsp8 complex is a unique multimeric RNA polymerase capable of both de novo initiation and primer extension. Nucleic acids research, 40: 1737–1747.
Thiel V, Ivanov K A, Putics A, Hertzig T, Schelle B, Bayer S, Weissbrich B, Snijder E J, Rabenau H, Doerr H W, Gorbalenya A E, Ziebuhr J. 2003. Mechanisms and enzymes involved in SARS coronavirus genome expression. J Gen Virol, 84: 2305–2315.
Wang F, Chen C, Liu X, Yang K, Xu X, Yang H. 2015. The crystal structure of feline infectious peritonitis virus main protease in complex with synergetic dual inhibitors. J Virol. doi: 10.1128/JVI.02685-15.
Woo PC, Lau SK, Huang Y, Yuen KY. 2009. Coronavirus diversity, phylogeny and interspecies jumping. Exp Biol Med (Maywood), 234: 1117–1127.
Woo PC, Lau SK, Lam CS, Lau CC, Tsang AK, Lau JH, Bai R, Teng JL, Tsang CC, Wang M, Zheng BJ, Chan KH, Yuen KY. 2012. Discovery of seven novel Mammalian and avian coronaviruses in the genus deltacoronavirus supports bat coronaviruses as the gene source of alphacoronavirus and betacoronavirus and avian coronaviruses as the gene source of gammacoronavirus and deltacoronavirus. J Virol, 86: 3995–4008.
Yang S, Chen SJ, Hsu MF, Wu JD, Tseng CT, Liu YF, Chen HC, Kuo CW, Wu CS, Chang LW, Chen WC, Liao SY, Chang TY, Hung HH, Shr HL, Liu CY, Huang YA, Chang LY, Hsu JC, Peters CJ, Wang AH, Hsu MC. 2006. Synthesis, crystal structure, structure-activity relationships, and antiviral activity of a potent SARS coronavirus 3CL protease inhibitor. J Med Chem, 49: 4971–4980.
Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD, Fouchier RA. 2012. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med, 367: 1814–1820.
Zhao Q, Weber E, Yang H. 2013a. Drug targets for rational design against emerging coronaviruses. Infect Disord Drug Targets, 13: 116–127.
Zhao Q, Weber E, Yang H. 2013b. Recent developments on coronavirus main protease/3C like protease inhibitors. Recent Pat Antiinfect Drug Discov, 8: 150–156.
Zhou L, Liu Y, Zhang W, Wei P, Huang C, Pei J, Yuan Y, Lai L. 2006. Isatin compounds as noncovalent SARS coronavirus 3Clike protease inhibitors. J Med Chem, 49: 3440–3443.
Ziebuhr J, 2004. Molecular biology of severe acute respiratory syndrome coronavirus. Curr Opin Microbiol, 7: 412–419.
Ziebuhr J. 2005. The coronavirus replicase. Curr Top Microbiol Immunol, 287: 57–94.
Ziebuhr J, Snijder EJ, Gorbalenya AE. 2000. Virus-encoded proteinases and proteolytic processing in the Nidovirales. J Gen Virol, 81: 853–879.
About this article
Cite this article
Wang, H., Xue, S., Yang, H. et al. Recent progress in the discovery of inhibitors targeting coronavirus proteases. Virol. Sin. 31, 24–30 (2016). https://doi.org/10.1007/s12250-015-3711-3
- main protease
- protease inhibitors