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

doi:10.6023/cjoc202202011

Chinese Journal of Organic Chemistry ›› 2022, Vol. 42 ›› Issue (7): 1974-1999.DOI: 10.6023/cjoc202202011 Previous Articles Next Articles

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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

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)

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

Cite this article

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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Fig. & Tab. 40

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

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

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

Figure 4. Subsite nomenclature for proteolytic enzymes

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

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

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

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

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

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

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

Figure 11. Chemical structure of inhibitor 9

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

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

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

Figure 14. Chemical structure of inhibitor 15

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

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

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

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

Figure 19. Chemical structures of inhibitors 20~26

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

Figure 21. Chemical structure of inhibitor 29

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

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

Figure 24. Chemical structure of cyclic peptides UCI-1

Figure 25. Chemical structure of indole inhibitor 33

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

Figure 27. Chemical structure of inhibitor 36

Figure 28. Chemical structures of inhibitors 37 and 38

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

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

Figure 31. Chemical structure of inhibitor 43

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

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

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

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

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

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

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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