小分子抗新型冠状病毒药物的突破性进展

doi:10.19803/j.1672-8629.2022.01.01

中国药物警戒 ›› 2022, Vol. 19 ›› Issue (1): 1-6.
DOI: 10.19803/j.1672-8629.2022.01.01

小分子抗新型冠状病毒药物的突破性进展

赵喆, 张清, 葛子若, 张伟, 陈志海^*

首都医科大学附属北京地坛医院感染性疾病临床中心,北京 100015

收稿日期:2021-11-18 出版日期:2022-01-15 发布日期:2022-01-20
通讯作者: ^*陈志海,男,硕士,主任医师,感染性疾病。E-mail：chenzhihai0001@126.com
作者简介:赵喆,女,在读硕士,感染性疾病。陈志海,主任医师,教授,博士生导师,长江学者奖励计划特聘教授。首都医科大学附属北京地坛医院感染性疾病临床中心主任,国家卫健委传染病标准专业委员会委员,中华预防医学会感染性疾病防控分会常务委员,中华医学会北京分会感染专业委员会副主任委员。致力于各种急性传染病临床诊治研究30余年,作为国家卫健委、北京市卫健委专家参加全国各种重大传染病疫情处置。新冠肺炎疫情以来,作为国家专家组、市级专家组成员,始终奋战在一线参加患者救治及疫情处置。在新冠肺炎领域作为第一主编编著专著2部,参与2项国家重点研发计划,以第一作者或通讯作者身份发表中英文论文16 篇（SCI 6篇）,参与完成《北京市新型冠状病毒肺炎病例临床路径》第一版、第二版。
基金资助:
国家重点研发计划（2020YFC0848300）; 首都卫生发展科研专项项目（2021-1G-4281）; 教育部2020年长江学者项目

Giant progress in small molecule antiviral drugs for SARS-CoV-2

ZHAO Zhe, ZHANG Qing, GE Ziruo, ZHANG Wei, CHEN Zhihai^*

Center of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China

Received:2021-11-18 Online:2022-01-15 Published:2022-01-20

摘要/Abstract

摘要： 目的研究蛋白酶抑制剂与依赖RNA的RNA聚合酶抑制剂两种抗新型冠状病毒药物。方法从作用机制、药代动力学、临床试验等方面对这两类小分子药物进行论述。结果在诸多抗新型冠状病毒药物中,小分子药物具有易吸收、分子体积小、能够穿透细胞膜、易于大规模工业化生产等优点,是药物研发的重点。在具有抗新型冠状病毒作用的小分子药物中,以病毒蛋白剪切步骤为作用靶点的蛋白酶抑制剂（如帕克洛维）与依赖RNA的RNA聚合酶抑制剂（如莫那匹韦）取得突破性进展。结论预期未来这类药物可在早期治疗中广泛应用,降低重症化率、降低病死率。

关键词: 小分子药物, 新型冠状病毒肺炎, 新型冠状病毒, 蛋白酶抑制剂, 聚合酶抑制剂, 临床试验

Abstract: Objective To study anti-SARS-CoV-2 drugs of protease inhibitors and RNA-dependent RNA polymerase inhibitors. Methods The mechanism of action, pharmacokinetics and clinical trials of two kind of drugs are reviewed. Results Small molecule drugs have the advantages of easy absorption, small molecular volume, ability to penetrate cell membrane, and easy large-scale industrial production, which are the focus of drug research and development. In the small-molecule drugs for SARS-CoV-2, breakthroughs have been made in protease inhibitors (such as Paxlovid) that target the viral protein splicing step and RNA-dependent RNA polymerase inhibitors (such as molnupiravir). Conclusion It is expected that these drugs can be widely used in early treatment in the future to reduce the rate of severe illness and mortality.

Key words: small molecule drugs, COVID-19, SARS-CoV-2, protease inhibitor, polymerase inhibitor, clinical trials

中图分类号:

R978.7

赵喆, 张清, 葛子若, 张伟, 陈志海. 小分子抗新型冠状病毒药物的突破性进展[J]. 中国药物警戒, 2022, 19(1): 1-6.

ZHAO Zhe, ZHANG Qing, GE Ziruo, ZHANG Wei, CHEN Zhihai. Giant progress in small molecule antiviral drugs for SARS-CoV-2[J]. Chinese Journal of Pharmacovigilance, 2022, 19(1): 1-6.

参考文献

[1] WHO. Weekly epidemiological update on COVID-19 - 9 November2021[EB/OL]. [2021-11-30]. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports.
[2] 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.
[3] SHANNON A, SELISKO B, LE N, et al.Favipiravir strikes the SARS-CoV-2 at its Achilles heel, the RNA polymerase[J]. BioRxiv, 2020(5): 098731.
[4] WU F, ZHAO S, YU B, et al.A new coronavirus associated with human respiratory disease in China[J]. Nature, 2020, 579(7798): 265-269.
[5] ZHOU P, YANG XL, WANG XG, et al.A pneumonia outbreak associated with a new coronavirus of probable bat origin[J]. Nature, 2020, 579: 270-273.
[6] PILLAIYAR T, MANICKAM M, NAMASIVAYAM V, et al.An overview of severe acute respiratory syndrome-coronavirus(SARS-CoV) 3CL protease inhibitors: peptidomimetics and small molecule chemotherapy[J]. J Med Chem, 2016, 59(14): 6595-6628.
[7] JIN Z, DU X, XU Y, et al.Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors[J]. 2020, 582(7811): 289-293.
[8] MA C, SACCO MD, XIA Z, et al.Discovery of SARS-CoV-2 papain-like protease inhibitors through a combination of high-throughput screening and a flipGFP-Based reporter assay[J]. ACS Cent Sci, 2021, 7(7): 1245-1260.
[9] MOUFFOUK C, MOUFFOUK S, MOUFFOUK S, et al.Flavonols as potential antiviral drugs targeting SARS-CoV-2 proteases (3CLpro and PLpro), spike protein, RNA-dependent RNA polymerase (RdRp) and angiotensin-converting enzyme II receptor (ACE2)[J]. Eur J Pharmacol, 2021, 891: 173759.
[10] MAHASE E.COVID-19: Pfizer's paxlovid is 89% effective in patients at risk of serious illness, company reports[J]. BMJ, 2021, 375: 2713.
[11] DEVRIES M, MOHAMED AS, PRESCOTT RA, et al.A comparative analysis of SARS-CoV-2 antivirals characterizes 3CL proinhibitor PF-00835231 as a potential new treatment for COVID-19[J]. J Virol, 2021, 95(10): e01819-01820.
[12] BARILLI A, VISIGALLI R, FERRARI F, et al.Organic cation transporters (OCTs) in EpiAirway™,a cellular model of normal human bronchial epithelium[J]. Biomedicines, 2020, 8(5): 127.
[13] OWEN DR, ALLERTON CMN, ANDERSON AS, et al. An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19[J]. Science, 2021(10): eabl4784.
[14] BANKER MJ, CLARK TH, WILLIAMS JA.Development and validation of a 96-well equilibrium dialysis apparatus for measuring plasma protein binding[J]. J Pharm Sci, 2003, 92(5): 967-974.
[15] National Institutes of Health (US). Coronavirus disease2019 (COVID-19) treatment guidelines[EB/OL].(2021-11-16)[2021-11-30]. https://www.ncbi.nlm.nih.gov/books/NBK570371/.
[16] KLEMM T, EBERT G, CALLEJA DJ, et al.Mechanism and inhibition of the papain-like protease, PLpro, of SARS-CoV-2[J]. EMBO J, 2020, 39(18): e106275.
[17] RUT W, LV Z, ZMUDZINSKI M, et al. Activity profiling and crystal structures of inhibitor-bound SARS-CoV-2 papain-like protease: a framework for anti-COVID-19 drug design[J]. Sci Adv, 2020, 6(42): eabd4596.
[18] HERNANDEZ-SANTIAGO BI, BELTRAN T, STUYVER L, et al.Metabolism of the anti-hepatitis C virus nucleoside beta-D-N4-hydroxycytidine in different liver cells[J]. Antimicrob Agents Chemother, 2004, 48(12): 4636-4642.
[19] PAINTER GR, BOWEN RA, BLUEMLING GR, et al.The prophylactic and therapeutic activity of a broadly active ribonucleoside analog in a murine model of intranasal Venezuelan equine encephalitis virus infection[J]. Antiviral Res, 2019, 171: 104597.
[20] 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]. Virol, 2019, 93(24): e01348-19.
[21] FERRON F, SUBISSI L, SILVEIRA DE MAT, et al.Structural and molecular basis of mismatch correction and ribavirin excision from coronavirus RNA[J]. Proc Natl Acad Sci USA, 2018, 115(2): E162-E171.
[22] SMITH EC, BLANC H, SURDEL MC, et al.Coronaviruses lacking exoribonuclease activity are susceptible to lethal mutagenesis: evidence for proofreading and potential therapeutics[J]. PLoS Pathog, 2014, 10(7): e1004342.
[23] GORDON CJ, TCHESNOKOV EP, SCHINAZI RF, et al.Molnup-iravir promotes SARS-CoV-2 mutagenesis via the RNA template[J]. J Biol Chem, 2021, 297(1): 100770.
[24] 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.
[25] MERCK. Merck and Ridgeback's Investigational Oral Antiviral Molnupiravir Reduced the Risk of Hospitalization or Death by Approximately 50 Percent Compared to Placebo for Patients with Mild or Moderate COVID-19 in Positive Interim Analysis of Phase 3 Study[EB/OL].(2021-10-01)[2021-11-30]. https://www.merck.com/news/merck-and-ridgebacks-investigational-oral-antiviral-molnupiravir-reduced-the-risk-of-hospitalization-or-death-by-approximately-50-percent-compared-to-placebo-for-patients-with-mild-or-moderat/.
[26] 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.
[27] KHOO SH, FITZGERALD R, FLETCHER T, et al.Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study[J]. J Antimicrob Chemother, 2021, 76(12): 3286-3295.
[28] FISCHER W, ERON JJ, HOLMAN W, et al.Molnupiravir, an oral antiviral treatment for COVID-19[J]. MedRxiv, 2021(6): 21258639.
[29] 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.
[30] Veklury (remdesivir). USprescribing information[EB/OL].(2020-10-22)[2021-11-30]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/214787Orig1s000lbl.pdf.
[31] SHEAHAN TP, SIMS AC, GRAHAM RL, et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses[J]. Sci Transl Med, 2017(9): eaal3653.
[32] LO MK, JORDAN R, ARVEY A, et al.GS-5734 and its parent nucleoside analog inhibit filo-, pneumo-, and paramyxoviruses[J]. Sci Rep, 2017(7): 43395.
[33] WARREN TK, JORDAN R, LO MK, et al.Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys[J]. Nature, 2016, 531: 381-385.
[34] GORDON CJ, TCHESNOKOV EP, WOOLNER E, et al.Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency[J]. J Biol Chem, 2020, 295: 6785-6797.
[35] BEIGEL JH, TOMASHEK KM, DODD LE, et al.ACTT-1 Study Group Members. Remdesivir for the treatment of COVID-19 - final report[J]. N Engl J Med, 2020, 383(19): 1813-1826.
[36] 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.
[37] PAN H, PETO R, HENAO-RESTREPO AM, et al.WHO Solidarity Trial Consortium. Repurposed antiviral drugs for COVID-19-interim WHO solidarity trial results[J]. N Engl J Med, 2020, 384: 497-511.
[38] WANG Y, ZHANG D, DU G, et al.Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial[J]. Lancet, 2020, 395: 1569-1578.
[39] SIMONIS A, THEOBALD SJ, FÄTKENHEUER G, et al. A comparative analysis of remdesivir and other repurposed antivirals against SARS-CoV-2[J]. EMBO Mol Med, 2021, 13(1): e13105.
[40] FDA. FDA approves first treatment for COVID-19[EB/OL].(2020-12-07)[2021-11-30]. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-covid-19. 7 Dec 2020.
[41] LAMB YN.Remdesivir: first approval[J]. Drugs, 2020, 80(13): 1355-1363.
[42] SHIRAKI K, DAIKOKU T.Favipiravir, an anti-influenza drug against life threatening RNA virus infections[J]. Pharmacol Ther, 2020, 22: 107512.
[43] MANLI W.Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus(2019-nCoV)in vitro[J]. Cell Research, 2020, 30: 269-271.
[44] WANG Y, FAN G, SALAM A, et al.Comparative effectiveness of combined favipiravir and oseltamivir therapy versus oseltamivir monotherapy in critically ill patients with influenza virus infection[J]. J Infect Dis, 2020, 221: 1688-1698.
[45] DU YX, CHEN XP.Favipiravir: pharmacokinetics and concerns about clinical trials for 2019-nCoV infection[J]. Clin Pharmacol Ther, 2020, 108: 242-247.
[46] JOSHI S, PARKAR J, ANSARI A, et al.Role of favipiravir in the treatment of COVID-19[J]. Int J Infect Dis, 2021, 102: 501-508.
[47] CAI Q, YANG M, LIU D, et al.Experimental treatment with favipiravir for COVID-19:an open-label control study[J]. Engineering(Beijing), 2020, 6(10): 1192-1198.
[48] YAMADA K.Anti-inflfluenza drug avigan tablet meets primary endpoint in phase iii clinical trial in Japan for COVID-19 patients[EB/OL]. [2021-11-30].https://asia.nikkei.com/Spotlight/Coronavirus/Japanese-approval-sought-for-Avigan-to-treatCOVID-19.

小分子抗新型冠状病毒药物的突破性进展

Giant progress in small molecule antiviral drugs for SARS-CoV-2

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

[1]	张敬升, 冀祖恩, 庞博, 徐英莉, 曹姗, 张宇, 孙绮悦, 孙静, 李舒冉, 张薇, 赵荣华, 崔晓兰. 宣肺败毒方治疗新冠病毒感染的中医学理论探讨及现代药理研究进展[J]. 中国药物警戒, 2024, 21(1): 55-58.
[2]	李舒冉, 郭姗姗, 冀祖恩, 张薇, 崔晓兰. 新型冠状病毒感染后认知功能障碍的研究现状[J]. 中国药物警戒, 2024, 21(1): 59-64.
[3]	刘敏, 陈艳, 刘文东, 王海学. 药物临床试验期间安全性数据快速报告的更新与思考[J]. 中国药物警戒, 2024, 21(1): 98-101.
[4]	陈华炎, 江东波, 郭春连, 杨家琪, 黎雨欣, 蔡伟明. 326例奈玛特韦片/利托那韦片治疗新型冠状病毒感染安全性分析[J]. 中国药物警戒, 2024, 21(1): 107-110.
[5]	马瑞泽, 陈志海. 抗新型冠状病毒的小分子药物最新研究进展[J]. 中国药物警戒, 2023, 20(9): 961-966.
[6]	沈艳杰, 吴奕卿. 临床试验期间不良事件管理的实践与思考[J]. 中国药物警戒, 2023, 20(9): 982-986.
[7]	刘文东, 崔欢欢, 王晓晗, 苏娴, 王海学. 我国儿童用药临床试验期间药物警戒监管体系现状及思考[J]. 中国药物警戒, 2023, 20(9): 1002-1006.
[8]	李婧, 徐烨, 刘冉佳, 潘晨, 崔向丽. 新型冠状病毒感染患者使用托珠单抗后发生不良反应的病例分析[J]. 中国药物警戒, 2023, 20(9): 1049-1053.
[9]	杨秋月, 苏俊, 张雪, 谢江安. 基于VAERS数据库的三类美国上市新型冠状病毒疫苗不良事件分析[J]. 中国药物警戒, 2023, 20(10): 1141-1147.
[10]	穆思聪, 王卓, 卢俊阳, 纪立伟, 柳鑫. 吡格列酮对2型糖尿病患者血浆脂联素影响的Meta分析[J]. 中国药物警戒, 2022, 19(9): 1015-1018.
[11]	葛子若, 田地, 王爱彬, 张婷玉, 任兴翔, 钱芳, 李兴旺, 陈志海. 干扰素雾化对新型冠状病毒肺炎的临床治疗分析[J]. 中国药物警戒, 2022, 19(7): 733-739.
[12]	王铁柱. 硫酸羟氯喹致视觉损害不良反应信号检测与分析[J]. 中国药物警戒, 2022, 19(6): 657-660.
[13]	赵暄, 郭婧, 梅隆, 张威. 自动发药系统对门诊药房工作效率和新型冠状病毒肺炎疫情防控的影响分析[J]. 中国药物警戒, 2022, 19(5): 564-567.
[14]	吴作敏, 杨娟, 王隆隆, 王瑞. 黄芪-防风药对治疗新型冠状病毒肺炎的网络药理学研究[J]. 中国药物警戒, 2022, 19(4): 395-399.
[15]	杨帆, 马海平, 尤萌茹, 廖沙, 刘兰, 朱军. 456例新型冠状病毒肺炎患者抗病毒药物应用分析[J]. 中国药物警戒, 2022, 19(4): 413-416.