靶向新型冠状病毒SARS-CoV-2主蛋白酶的抗病毒药物研究进展

doi:10.6023/cjoc202202011

有机化学 ›› 2022, Vol. 42 ›› Issue (7): 1974-1999.DOI: 10.6023/cjoc202202011 上一篇下一篇

综述与进展

靶向新型冠状病毒SARS-CoV-2主蛋白酶的抗病毒药物研究进展

王春霞^a^,^b, 胡晓东^b, 许斌^a^,^*(), 曹春阳^b^,^*()

^a上海大学理学院化学系上海 200444
^b中国科学院上海有机化学研究所生命有机化学国家重点实验室上海 200032

收稿日期:2022-02-16 修回日期:2022-04-06 发布日期:2022-08-09
通讯作者: 许斌, 曹春阳
基金资助:
科技部重点研发项目(2017YFE0108200); 中国科学院战略性先导科技专项(XDB20000000); 国家自然科学基金(21977110); 国家自然科学基金(22177127); 国家自然科学基金(91753119); 及中国科学院分子合成卓越中心(FZHCZY020600)

Research Progress of Antiviral Drug Targeting the Main Protease of SARS-CoV-2

Chunxia Wang^a^,^b, Xiaodong Hu^b, Bin Xu^a(), Chunyang Cao^b()

^aDepartment of Chemistry, College of Science, Shanghai University, Shanghai 200444
^bState Key Lab of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032

Received:2022-02-16 Revised:2022-04-06 Published:2022-08-09
Contact: Bin Xu, Chunyang Cao
Supported by:
National Key Research and Development Program of Ministry of Science and Technology(2017YFE0108200); Chinese Academy of Sciences Strategic Priority Research Program(XDB20000000); National Natural Science Foundation of China(21977110); National Natural Science Foundation of China(22177127); National Natural Science Foundation of China(91753119); Center for Excellence in Molecular Synthesis, Chinese Academy of Sciences(FZHCZY020600)

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摘要/Abstract

2019年底, 新型冠状病毒SARS-CoV-2导致的新冠肺炎大流行对世界人口产生了严重的威胁. 目前一些有效的疫苗已被批准并广泛使用, 但考虑到冠状病毒的高突变性, 这一干预措施的长期有效性和安全性存在争议. 此外一些抗病毒药物显示出较好的效果, 但其安全性与普适性暂未得到更多的数据支持. 冠状病毒主蛋白酶(3CL^pro)是冠状病毒家族中一种特殊的半胱氨酸蛋白酶, 负责处理病毒多蛋白产生成熟的非结构蛋白, 在冠状病毒生命周期中起重要作用, 而且具有高度保守性, 因此其是一个重要的药物靶点. 结构研究为这种蛋白酶的功能和合理抑制剂设计的结构基础提供了有价值的见解. 综述了SARS-CoV-2 3CL^pro的结构和迄今为止针对3CL^pro的亮点抑制剂的研究进展, 并详细介绍了抑制剂与3CL^pro的结合方式和构效关系. 此外, 还广泛研究了这些抑制剂的抗病毒活性、ADMET和动物试验.

关键词: 新冠肺炎, 新型冠状病毒, 主蛋白酶抑制剂, 抗病毒药物发现

The COVID-19 pandemic caused by the novel coronavirus SARS-CoV-2 in late 2019 posed a serious threat to the world population. Some effective vaccines are currently approved and widely used, but the long-term efficacy and safety of this intervention is controversial given the highly mutagenic nature of the coronavirus. In addition, some antiviral drugs show better effects, but their safety and universality have not been supported by more data. Coronavirus main protease (3CL^pro) is a special cysteine protease in the coronavirus family, responsible for processing viral polyproteins to produce yield mature non-structural proteins, which play an important role in the life cycle of coronaviruses and are highly conserved, and therefor is considered as a prominent target for antiviral drug. Strucure studies provide valuable insight into the function of this protease and structural basis of rational inhibitor design. This paper reviews the structure of SARS-CoV-2 3CL^pro and the research progress of bright spot inhibitors targeting 3CL^pro so far, and introduces binding mode and the structure-activity relationships of inhibitors and 3CL^pro in detail. Additionally, we broadly examine available antiviral activity, ADMET and animal tests of these inhibitors.

Key words: COVID-19, SARS-CoV-2, 3CL^pro inhibitor, antivirals drug discovery

引用此文

王春霞, 胡晓东, 许斌, 曹春阳. 靶向新型冠状病毒SARS-CoV-2主蛋白酶的抗病毒药物研究进展[J]. 有机化学, 2022, 42(7): 1974-1999.

Chunxia Wang, Xiaodong Hu, Bin Xu, Chunyang Cao. Research Progress of Antiviral Drug Targeting the Main Protease of SARS-CoV-2[J]. Chinese Journal of Organic Chemistry, 2022, 42(7): 1974-1999.

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图/表 40

图1. SARS-CoV-2复制周期的示意图

Figure 1. Sketched view of the SARS-CoV-2 replication cycle

图2. (a)由SARS-CoV-2基因组编码的病毒蛋白[图中显示了非结构蛋白(nsps)、结构蛋白和辅助蛋白(Orf3a到Orf9b)]和(b)几种非结构蛋白的膜拓扑结构

Figure 2. (a) Viral proteins encoded by the viral genome (the nonstructural proteins (nsps), structural proteins and accessory proteins (Orf3a to Orf9b) are shown) and (b) membrane topology of several nonstructural proteins The transmembrane domains of proteins are shown as cylinders. Arrows indicate cleavage sites of PLpro (green) and 3CLpro (red). Other nonstructural proteins are shown as spheres

图3. SARS-CoV-2 3CLpro的晶体结构

Figure 3. Crystal structure of SARS-CoV-2 3CLpro One protomer of the dimer is shown in brightorgane, and domains I, II and III of the other one are shown in marine, green and violet

图4. 蛋白水解酶的亚位点命名法

Figure 4. Subsite nomenclature for proteolytic enzymes

图5. SARS-CoV-2 3CLpro的水解机理

Figure 5. Hydrolysis mechanism of SARS-CoV-2 3CLpro

图6. 重新用于治疗COVID-19的FDA批准的药物

Figure 6. FDA-approved drugs repurposed for the treatment of COVID-19

图7. (a)抑制剂1 (N3)化学结构和(b) N3与SARS-CoV-2 3CLpro复合物晶体结构域

Figure 7. (a) Structure of inhibitor 1 (N3), and (b) crystal structure of N3 in complex with SARS-CoV-2 3CLpro Hydrogen bonds are depicted by black dashed lines

图式1. 亚硫酸氢盐前药GC373转化为3CLpro的醛类抑制剂GC376

Scheme 1. Bisulfite compound GC376 converts into the aldehyde inhibitor GC373 of 3CLpro

图8. GC376与SARS-CoV-2 3CLpro的复合物晶体结构

Figure 8. Crystal structure of GC376 in complex with SARS- CoV-2 3CLpro Hydrogen bonds are depicted by black dashed lines

图9. 抑制剂4、5、6的化学结构及4与SARS-CoV-2 3CLpro复合物的X射线晶体结构

Figure 9. Chemical structures of inhibitors 4, 5, 6 and crystal structure of inhibitor 4 in complex with SARS-CoV-2 3CLpro

图10. (a)抑制剂7和8化学结构和(b) 7与SARS-CoV-2 3CLpro复合物晶体结构

Figure 10. (a) Structures of inhibitors 7 and 8, and (b) crystal structure of inhibitor 7 in complex with SARS-CoV-2 3CLpro Hydrogen bonds are depicted by black dashed lines

图11. 抑制剂9的化学结构

Figure 11. Chemical structure of inhibitor 9

图12. (a)抑制剂10的化学结构和(b)抑制剂10与SARS-CoV- 2 3CLpro复合物晶体结构

Figure 12. (a) Structure of inhibitor 10 and (b) crystal structure of inhibitor 10 in complex with SARS-CoV-2 3CLpro Hydrogen bonds are depicted by black dashed lines

图式2. 靶向3CLpro的α-酮酰胺弹头抑制剂的设计

Scheme 2. Design of 3CLpro inhibitors bearing a α-ketoamide as warhead

图13. 13与SARS-CoV-2 3CLpro复合物晶体结构

Figure 13. Crystal structure of 13 in complex with SARS-CoV- 2 3CLpro Hydrogen bonds are depicted by black dashed lines

图14. 抑制剂15的化学结构

Figure 14. Chemical structure of inhibitor 15

图15. (a)抑制剂16的化学结构, 以及(b)抑制剂16和SARS CoV-2 3CLpro与SARS-CoV 3CLpro之间结合的总体变化

Figure 15. (a) Chemical structure of inhibitor 16, and (b) overall shifts in inhibitor 16 binding between inhibitor 16 and SARS- CoV-2 3CLpro and SARS-CoV 3CLpro Overall shifts emphasized with blue arrows

图16. (a)抑制剂17的化学结构和(b)抑制剂17与SARS-CoV- 2 3CLpro复合物晶体结构

Figure 16. (a) Chemical structure of inhibitor 17, and (b) crystal structure of inhibitor 17 in complex with SARS-CoV-2 3CLpro Surface charge analysis of SARS-CoV-2 3CLpro is shown using PyMOL

图17. (a)抑制剂18和19的化学结构和(b)抑制剂18与SARS-CoV-2 3CLpro复合物晶体结构

Figure 17. (a) Chemical structures of inhibitors 18 and 19, and (b) crystal structure of inhibitor 18 in complex with SARS-CoV-2 3CLpro 2Fo-Fc electron density map is shown in gray

图18. (a)羟甲基酮化合物20和其磷酸酯前药21化学结构, 以及(b)抑制剂20与SARS-CoV-2 3CLpro复合物晶体结构

Figure 18. (a) Chemical structures of hydroxymethyl ketone compound 20 and phosphate prodrug 21, (b) crystal structure of inhibitor 20 in complex with SARS-CoV-2 3CLpro

图19. 抑制剂20~26的化学结构

Figure 19. Chemical structures of inhibitors 20~26

图20. (a)腈弹头抑制剂27和28的化学结构式, 以及(b) 28与SARS-CoV-2 3CLpro复合物晶体结构

Figure 20. (a) Chemical structures of nitrile warheads inhibitors 27 and 28, and (b) crystal structure of inhibitor 28 in complex with SARS-CoV-2 3CLpro

图21. 抑制剂29的化学结构

Figure 21. Chemical structure of inhibitor 29

图22. (a)抑制剂30的化学结构式, 以及(b)抑制剂30与SARS-CoV-2 3CLpro复合物晶体结构

Figure 22. (a) Chemical structure of inhibitor 30, and (b) crystal structure of inhibitor 30 in complex with SARS-CoV-2 3CLpro

图23. (a)抑制剂31的化学结构式, 以及(b)抑制剂31与SARS-CoV-2 3CLpro复合物晶体结构

Figure 23. (a) Chemical structure of inhibitor 31, and (b) crystal structure of inhibitor 31 in complex with 3CLpro Hydrogen bonds are depicted by black dashed line, water is depicted by red sphere

图24. 环状肽抑制剂UCI-1的化学结构式

Figure 24. Chemical structure of cyclic peptides UCI-1

图25. 吲哚化合物33的化学结构式

Figure 25. Chemical structure of indole inhibitor 33

图26. (a)化合物34和35的化学结构, (b)抑制剂35与SARS-CoV-2的晶体结构的表面静电势, (c)抑制剂35与SARS-CoV-2的晶体结构

Figure 26. (a) Chemical structures of compounds 34 and 35, (b) surface electrostatic potential of inhibitor 35 and SARS-CoV-2 complex crystal structure, (c) crystal structure of inhibitor 35 in complex with SARS-CoV-2 3CLpro Hydrogen bonds are depicted by black dashed line, water is depicted by red sphere

图27. 抑制剂36的化学结构式

Figure 27. Chemical structure of inhibitor 36

图28. 抑制剂37和38的化学结构

Figure 28. Chemical structures of inhibitors 37 and 38

图29. (a)黄芩苷39和黄芩素40的化学结构, 以及(b)黄芩素与3CLpro的主要相互作用

Figure 29. (a) Chemical structures of baicalin 39 and baicalein 40, and (b) the main interactions between baicalein and 3CLpro Hydrogen bonds are depicted by black dashed line, water is depicted by red sphere and π-π stacking interaction is depicted by yellow dashed line

图30. (a)抑制剂41和42的化学结构, 以及(b)抑制剂41与3CLpro主要相互作用

Figure 30. (a) Chemical structures of inhibitors 41 and 42, and (b) the main interactions between inhibitor 41 and 3CLpro Hydrogen bonds are depicted by black dashed line, water is depicted by red sphere and π-π stacking interaction is depicted by yellow dashed line

图31. 抑制剂43的化学结构

Figure 31. Chemical structure of inhibitor 43

图32. (a)抑制剂44转化为化合物45, 以及(b)化合物45与3CLpro复合物的晶体结构

Figure 32. (a) Conversion of inhibitor 44 to compound 45, and (b) crystal structure of 45 and 3CLpro Hydrogen bonds are depicted by red dashed

图式3. 化合物44在3CLpro结合口袋内的反应机制

Scheme 3. Reaction mechanism of biochemical activation of 44 within the 3CLpro binding pocket

图33. (a)紫草素的化学结构, 以及(b)紫草素和3CLpro之间的主要相互作用

Figure 33. (a) Chemical structure of shikonin, and (b) the main interactions between shikonin and 3CLpro Hydrogen bonds are depicted by black dashed line, p-i stacking interaction is depicted by yellow line

图34. 靛红化合物47, 48和49的化学结构

Figure 34. Chemical structures of isatin compounds 47, 48 and 49

图35. 抑制剂50(曲古抑菌素A)和3CLpro-C145之间的共价反应示意图

Figure 35. Illustration of the covalent reaction between inhibitor 50 (trichostatin A) and 3CLpro-C145

图36. 9,10-二氢菲衍生物51和52的化学结构

Figure 36. Chemical structures of 9,10-dihydrophenanthrene derivatives 51 and 52

图式4. 目标化合物55的基于结构的优化和化合物的概况

Scheme 4. Structure-based optimization of the hit compound 55 and the profiles of compounds

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靶向新型冠状病毒SARS-CoV-2主蛋白酶的抗病毒药物研究进展

Research Progress of Antiviral Drug Targeting the Main Protease of SARS-CoV-2

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