The latest progress of small molecule anti-SARS-CoV-2 drugs

doi:10.19803/j.1672-8629.20230357

Abstract

Abstract: Objective To study the main small molecule anti-SARS-CoV-2 drugs. Methods Aiming at the molecular structure and infection mechanism of SARS-CoV-2, we discussed and summarized the small molecule drugs from the aspects of blocking virus mechanism and clinical effect. Results According to the characteristics of the current variants of SARS-CoV-2, small molecule drugs were showing great potential with their unique advantages. Focusing on protease inhibitors and RNA-dependent RNA polymerase inhibitors, significant progress has been made in the research and development of new and old anti-SARS-CoV-2 small molecule drugs. Conclusions mall molecule anti-SARS-CoV-2 drugs can be used as a powerful weapon to fight the COVID-19 epidemic, and the early application of small molecule drugs can effectively improve clinical symptoms, reduce severe disease, hospitalization and mortality rate.

Key words: SARS-CoV-2, infection, small molecule drugs, clinical trials

CLC Number:

R978.7

MA Ruize, CHEN Zhihai. The latest progress of small molecule anti-SARS-CoV-2 drugs[J]. Chinese Journal of Pharmacovigilance, 2023, 20(9): 961-966.

References

[1] Johns Hopkins University. COVID-19 dashboard by the center for systems science and engineering (CSSE) at Johns Hopkins University (JHU)[EB/OL].(2023-03-10)[2023-03-10].https://coronavirus.Edu/map.htm.
[2] LU R, ZHAO X, LI J, et al.Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding[J]. Lancet, 2020, 395(10224): 565-574.
[3] KUMAR V, PARATE S, YOON S, et al.Computational simulations identified marine-derived natural bioactive compounds as replication inhibitors of SARS-CoV-2[J]. Front Microbiol, 2021, 12: 647295.
[4] HOFFMANN M, KLEINE-WEBER H, SCHROEDER S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor[J]. Cell, 2020, 181(2): 271-280.e8.
[5] CLAUSEN TM, SANDOVAL DR, SPLIID CB, et al. SARS-CoV-2 infection depends on cellular heparan sulfate and ACE2[J]. Cell, 2020, 183(4): 1043-1057.e15.
[6] KIRCHDOERFER RN, WARD AB. structure of the SARS-CoV nsp12 polymerase bound to nsp7 and nsp8 co-factors[J]. Nat Commun, 2019, 10(1): 2342.
[7] FREITAS BT, DURIE IA, MURRAY J, et al.Characterization and noncovalent inhibition of the deubiquitinase and deISGylase activity of SARS-CoV-2 papain-like protease[J]. ACS Infect Dis, 2020, 6(8): 2099-2109.
[8] Guidelines for the diagnosis and treatment of coronavirusdisease 2019(trial version ninth)[J]. Chinese Journal of Viral Diseases(中国病毒病杂志), 2022, 12(3): 161-169.
[9] ZHANG JL, LI YH, WANG LL, et al.Azvudine is a thymus-homing anti-SARS-CoV-2 drug effective in treating COVID-19 patients[J]. Signal Transduct Target Ther, 2021, 6(1): 414.
[10] SMITH DB, KALAYANOV G, SUND C, et al.The design, synthesis, and antiviral activity of monofluoro and difluoro analogues of 4'-azidocytidine against hepatitis C virus replication: the discovery of 4'-azido-2'-deoxy-2'-fluorocytidine and 4'-azido-2'-dideoxy-2',2'-difluorocytidine[J]. J Med Chem, 2009, 52(9): 2971-2978.
[11] XU N, YANG J, ZHENG B, et al.The pyrimidine analog FNC potently inhibits the replication of multiple enteroviruses[J]. J Virol, 2020, 94(9): e00204-e00220.
[12] TAO L, LI Y, GUO X, et al.Synthesis and anti-CVB3 activity of 4-amino acid derivative substituted pyrimidine nucleoside analogues[J]. Bioorg Med Chem Lett, 2020, 30(1): 126770.
[13] WANG J, XU WF, JIN PF.The first domestic original drug for the treatment of COVID-19: Azvudine[J]. Chinese Pharmaceutical Journal(中国药学杂志), 2022, 57(23): 2041-2044.
[14] YANG L, WANG Z.Bench-to-bedside: innovation of small molecule anti-SARS-CoV-2 drugs in China[J]. Eur J Med Chem, 2023, 257: 115503.
[15] VICENTI I, ZAZZI M, SALADINI F.SARS-CoV-2 RNA-dependent RNA polymerase as a therapeutic target for COVID-19[J]. Expert Opin Ther Pat, 2021, 31(4): 325-337.
[16] GORDON CJ, TCHESNOKOV EP, SCHINAZI RF, et al.Molnupiravir promotes SARS-CoV-2 mutagenesis via the RNA template[J]. J Biol Chem, 2021, 297(1): 100770.
[17] KABINGER F, STILLER C, SCHMITZOVÁ J, et al.Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis[J]. Nat Struct Mol Biol, 2021, 28(9): 740-746.
[18] PAINTER WP, HOLMAN W, BUSH JA, et al.Human safety, tolerability, and pharmacokinetics of molnupiravir, a novel broad-spectrum oral antiviral agent with activity against SARS-CoV-2[J]. Antimicrob Agents Chemother, 2021, 65(5): e02428-20.
[19] AGOSTINI ML, PRUIJSSERS AJ, CHAPPELL JD, et al.Small-molecule antiviral β-d-N4-hydroxycytidine inhibits a proofreading-intact coronavirus with a high genetic barrier to resistance[J]. J Virol, 2019, 93(24): e01348-19.
[20] WAHL A, GRALINSKI LE, JOHNSON CE, et al.SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801[J]. Nature, 2021, 591(7850): 451-457.
[21] JAYK BERNAL A, GOMES DA SILVA MM, MUSUNGAIE DB, et al. Molnupiravir for oral treatment of COVID-19 in nonhospitalized patients[J]. N Engl J Med, 2022, 386(6): 509-520.
[22] SINGH AK, SINGH A, SINGH R, et al.Molnupiravir in COVID-19: A systematic review of literature[J]. Diabetes Metab Syndr, 2021, 15(6): 102329.
[23] KHOO SH, FITZGERALD R, SAUNDERS G, et al.Molnupiravir versus placebo in unvaccinated and vaccinated patients with early SARS-CoV-2 infection in the UK (AGILE CST-2): a randomized, placebo-controlled, double-blind, phase 2 trial[J]. Lancet Infect Dis, 2023, 23(2): 183-195.
[24] DONOVAN-BANFIELD I, PENRICE-RANDAL R, GOLDSWAIN H, et al.Characterisation of SARS-CoV-2 genomic variation in response to molnupiravir treatment in the AGILE Phase IIa clinical trial[J]. Nat Commun, 2022, 13(1): 7284.
[25] ZHOU S, HILL CS, SARKAR S, et al.β-d-N4-hydroxycytidine inhibits SARS-CoV-2 through lethal mutagenesis but is also mutagenic to mammalian cells[J]. J Infect Dis, 2021, 224(3): 415-419.
[26] BEIGEL JH, TOMASHEK KM, DODD LE, et al.Remdesivir for the treatment of COVID-19 - final report[J]. N Engl J Med, 2020, 383(19): 1813-1826.
[27] HUMENIUK R, MATHIAS A, KIRBY BJ, et al.Pharmacokinetic, pharmacodynamic, and drug-interaction profile of Remdesivir, a SARS-CoV-2 replication inhibitor[J]. Clin Pharmacokinet, 2021, 60(5): 569-583.
[28] ZHAO Z, ZHANG Q, GE ZR, et al.Giant progress in small molecule antiviral drugs for SARS-CoV-2[J]. Chinese Journal of Pharmacovigilance(中国药物警戒), 2022, 19(1): 1-6.
[29] GRUNDEIS F, ANSEMS K, DAHMS K, et al. Remdesivir for the treatment of COVID-19[J]. Cochrane Database Syst Rev, 2023, 1(1): CD014962.
[30] ADER F, BOUSCAMBERT-DUCHAMP M, HITES M, et al.Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial[J]. Lancet Infect Dis, 2022, 22(2): 209-221.
[31] LA TESSA A, MOTISI MA, MARSEGLIA GL, et al.Use of remdesivir in children with COVID-19 infection: a quick narrative review[J]. Acta Biomed, 2021, 92(S7): e2021524.
[32] WANG Z, YANG L, SONG XQ.Oral GS-441524 derivatives: Next-generation inhibitors of SARS-CoV-2 RNA-dependent RNA polymerase[J]. Front Immunol, 2022, 13: 1015355.
[33] NMPA Conditionally approved the marketing of the combined packaging of Xianotevir Tablets/Ritonavir Tablets and Remidvir Deuterate Hydrobromide Tablets, a treatment drug for COVID-19 infection [EB/OL].(2023-02-07)[2023-03-10]. https://www.nmpa.gov.cn/zhuanti/yqjzx/yqyjxd/20230129143814163.html.
[34] SHEN Y, AI J, LIN N, et al.An open, prospective cohort study of VV116 in Chinese participants infected with SARS-CoV-2 omicron variants[J]. Emerg Microbes Infect, 2022, 11(1): 1518-1523.
[35] CAO Z, GAO W, BAO H, et al.VV116 versus Nirmatrelvir-Ritonavir for oral treatment of COVID-19[J]. N Engl J Med, 2023, 388(5): 406-417.
[36] QIAN HJ, WANG Y, ZHANG MQ, et al.Safety, tolerability, and pharmacokinetics of VV116, an oral nucleoside analog against SARS-CoV-2, in Chinese healthy subjects[J]. Acta Pharmacol Sin, 2022, 43(12): 3130-3138.
[37] HILGENFELD R.From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design[J]. FEBS J, 2014, 281(18): 4085-4096.
[38] ANAND K, ZIEBUHR J, WADHWANI P, et al.Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs[J]. Science, 2003, 300(5626): 1763-1767.
[39] SEVRIOUKOVA IF, POULOS TL.Structure and mechanism of the complex between cytochrome P4503A4 and ritonavir[J]. Proc Natl Acad Sci U S A, 2010, 107(43): 18422-18427.
[40] Pfizer Inc. Pfizer Announces Additional Phase 2/3 Study Results Confirming Robust Efficacy of Novel COVID-19 Oral Antiviral Treatment Candidate in Reducing Risk of Hospitalization or Death[EB/OL]. (2021-12-14)[ 2023-03-10].https://www.pfizer.com/news/press-release/press-release-detail/pfizer-announces-additional-phase-23-study-results.
[41] Food and drug administration. Food and Drug Administration Fact Sheet for Healthcare Providers: Emergency Use Authorization for Paxlovid[EB/OL]. (2022-01-18)[2023-03-10]. https://www.fda.gov/media/155050/download.
[42] HAMMOND J, LEISTER-TEBBE H, GARDNER A, et al.Oral Nirmatrelvir for high-risk, nonhospitalized adults with COVID-19[J]. N Engl J Med, 2022, 386(15): 1397-1408.
[43] DRYDEN-PETERSON S, KIM A, KIM AY, et al.Nirmatrelvir plus ritonavir for early COVID-19 in a large U.S. health system: a population-based cohort study[J]. Ann Intern Med, 2023, 176(1): 77-84.
[44] CHANG JB.Advances of oral small molecule drug for the treatment of COVID-19[J]. Bulletin of National Natural Science Foundation of China(中国科学基金), 2022, 36(4): 630-634.
[45] UNOH Y, UEHARA S, NAKAHARA K, et al.Discovery of S-217622, a noncovalent oral SARS-CoV-2 3CL protease inhibitor clinical candidate for treating COVID-19[J]. Med Chem, 2022, 65(9): 6499-6512.
[46] URAKI R, KISO M, IIDA S, et al.Characterization and antiviral susceptibility of SARS-CoV-2 Omicron BA.2[J]. Nature, 2022,607(7917):119-127.
[47] SHIMIZU R, SONOYAMA T, FUKUHARA T, et al.Safety, tolerability, and pharmacokinetics of the novel antiviral agent ensitrelvir fumaric acid, a SARS-CoV-2 3CL protease inhibitor, in healthy adults[J]. Antimicrob Agents Chemother, 2022, 66(10): e0063222.
[48] WANG F, XIAO W, TANG Y, et al.Efficacy and safety of SIM0417 (SSD8432) plus ritonavir for COVID-19 treatment: a randomised, double-blind, placebo-controlled, phase 1b trial[J]. Lancet Reg Health West Pac, 2023, 38: 100835.