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Review
. 2021 Apr 22;379(3):23.
doi: 10.1007/s41061-021-00335-9.

Insights into SARS-CoV-2: Medicinal Chemistry Approaches to Combat Its Structural and Functional Biology

Lin-Sheng Zhuo #  1 , Ming-Shu Wang #  1 , Jing-Fang Yang  1 , Hong-Chuang Xu  1 , Wei Huang  1 , Lu-Qing Shang  2 , Guang-Fu Yang  3
Affiliations
Review

Insights into SARS-CoV-2: Medicinal Chemistry Approaches to Combat Its Structural and Functional Biology

Lin-Sheng Zhuo et al. Top Curr Chem (Cham). .

Abstract

Coronavirus disease 2019, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is still a pandemic around the world. Currently, specific antiviral drugs to control the epidemic remain deficient. Understanding the details of SARS-CoV-2 structural biology is extremely important for development of antiviral agents that will enable regulation of its life cycle. This review focuses on the structural biology and medicinal chemistry of various key proteins (Spike, ACE2, TMPRSS2, RdRp and Mpro) in the life cycle of SARS-CoV-2, as well as their inhibitors/drug candidates. Representative broad-spectrum antiviral drugs, especially those against the homologous virus SARS-CoV, are summarized with the expectation they will drive the development of effective, broad-spectrum inhibitors against coronaviruses. We are hopeful that this review will be a useful aid for discovery of novel, potent anti-SARS-CoV-2 drugs with excellent therapeutic results in the near future.

Keywords: Antiviral; COVID-19; Drug discovery; SARS-CoV-2; Structural biology.

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Conflict of interest statement

The authors declare that they have no competing financial interests.

Figures

Fig. 1
Fig. 1
The life cycle of SARS-CoV-2, including: membrane fusion, endocytosis, uncoating, translation of RNA, proteolysis, assembly and exocytosis
Fig. 2
Fig. 2
a Cryo-EM structure of the SARS-CoV-2 S protein in the prefusion conformation (PDB ID 6VSB) [15]; b an overlay of RBDs from SARS-CoV-2 and SARS-CoV based on the position of their respective adjacent NTD: SARS-CoV-2 RBD (green), SARS-CoV RBD (white), SARS-CoV-2 NTD (purple), SARS-CoV NTD (white) [15]
Fig. 3
Fig. 3
The three structures of S protein of SARS-CoV-2 are calculated from micrographs of furin-cleaved material: a closed (PDB ID 6ZGI); b intermediate (PDB ID 6ZGH); c open (PDB ID 6ZGG) forms. The three monomers are colored orange, light blue and pale green [24]
Fig. 4
Fig. 4
a The co-crystal structures of SARS-CoV-2 RBD in complex with ACE2. b Superposition of the ridge in SARS-CoV RBM (yellow) and SARS-CoV-2 RBM (cyan). c Superposition of the ridge from another visual angle (PDB ID 6VW1) [33]
Fig. 5
Fig. 5
Reported compounds that block the SARS-CoV-2 cell entry
Fig. 6
Fig. 6
Cryo-EM structure of the nsp12-nsp7-nsp8 complex of SARS-CoV-2 (PDB ID 6M71) [56]
Fig. 7
Fig. 7
a Remdesivir monophosphate is covalently combined with the primer; b X-ray co-crystal structure of RNA bound RdRp in complex with remdesivir (PDB ID 7BV2) [57]
Fig. 8
Fig. 8
The structures of representative RdRp inhibitors
Fig. 9
Fig. 9
The proposed binding modes of inhibitors [ribavirin (a), EIDD-2081 (b), galidesivir (c), favipiravir (d), sofosbuvir (e) and IDX-184 (f)] with RdRp (PDB ID 7BV2)
Fig. 10
Fig. 10
a The structure of one monomer of the dimeric SARS-CoV-2 Mpro with inhibitor N3 (PDB ID 6LU7) [82]; b the chemical structure of N3 inhibitor; c the inhibitor-free crystal structure of the dimeric SARS-CoV-2 Mpro (PDB ID 6Y2E) [89]
Fig. 11
Fig. 11
a Structures of α-ketoamide inhibitors 12, 13, 14 and 15 (the modification process is highlighted with background color); b co-crystal structure of inhibitor 14 in the active site of SARS-CoV-2 Mpro (PDB: 6Y2F) [89]
Fig. 12
Fig. 12
Medicinal chemistry information of novel peptidomimetic-based inhibitors 16a–b against SARS-CoV-2 Mpro from design to candidates
Fig. 13
Fig. 13
The structures of GC376 a and boceprevir c; Co-crystal structures of GC376 b (PDB ID: 7C6S) and boceprevir d (PDB ID: 7C6U) in the active site of SARS-CoV-2 Mpro
Fig. 14
Fig. 14
a The chemical structure of carmofur; b co-crystal structures of carmofur in the active site of SARS-CoV-2 Mpro (PDB ID: 7BUY)
Fig. 15
Fig. 15
The structures of representative peptidomimetic inhibitors 20–28 incorporating various warheads (identified in pink clouds)
Fig. 16
Fig. 16
The structures of small-molecule inhibitors 29–32 against SARS-CoV Mpro (warheads are identified in pink clouds)
Fig. 17
Fig. 17
a The chemical structures of representative non-peptide SARS-CoV Mpro inhibitors; b superposition of co-crystal structures of N3 (yellow, PDB ID: 2HOB) and compound 33 (violet, PDB ID: 4TWY) with SARS-CoV Mpro; c superposition of co-crystal structures of N3 (yellow) and compound 34 (cyan, PDB ID: 3V3M) with SARS-CoV Mpro; d superposition of co-crystal structures of N3 (yellow) and compound 35 (pale green, PDB ID: 4MDS) with SARS-CoV Mpro. The H bonds are colored in wheat or green
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