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Review
. 2020 Nov 12;63(21):12256-12274.
doi: 10.1021/acs.jmedchem.0c00502. Epub 2020 Jun 25.

Inhibitors of SARS-CoV-2 Entry: Current and Future Opportunities

Siyu Xiu  1 , Alexej Dick  2 , Han Ju  1 , Sako Mirzaie  3 , Fatemeh Abdi  4 , Simon Cocklin  2 , Peng Zhan  1 , Xinyong Liu  1
Affiliations
Review

Inhibitors of SARS-CoV-2 Entry: Current and Future Opportunities

Siyu Xiu et al. J Med Chem. .

Abstract

Recently, a novel coronavirus initially designated 2019-nCoV but now termed SARS-CoV-2 has emerged and raised global concerns due to its virulence. SARS-CoV-2 is the etiological agent of "coronavirus disease 2019", abbreviated to COVID-19, which despite only being identified at the very end of 2019, has now been classified as a pandemic by the World Health Organization (WHO). At this time, no specific prophylactic or postexposure therapy for COVID-19 are currently available. Viral entry is the first step in the SARS-CoV-2 lifecycle and is mediated by the trimeric spike protein. Being the first stage in infection, entry of SARS-CoV-2 into host cells is an extremely attractive therapeutic intervention point. Within this review, we highlight therapeutic intervention strategies for anti-SARS-CoV, MERS-CoV, and other coronaviruses and speculate upon future directions for SARS-CoV-2 entry inhibitor designs.

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Figures

Figure 1.
Figure 1.
Countries with reported SARS-CoV-2 infections. Countries with reported infections in blue and countries/areas with no reported infections in yellow (North Korea, Turkmenistan, and Western Sahara).
Figure 2.
Figure 2.
Structure of the SARS-CoV-2 Spike (S) protein in its prefusion conformation (PDB 6VSB). (A) Cryo-EM structure of the trimeric and monomeric S protein and (B) domain architecture with colored domains and not resolved/missing regions in white. NTD, N-terminal domain; RBD, receptor-binding domain; FP, fusion peptide region; HR1/2, heptad repeat 1/2; TM, transmembrane domain S1/S2; S2′: protease cleavage sites. (C) Structural alignment of SARS-CoV-2 S (in orange and HR1 in dark-blue, PDB 6VSB) and SARS-CoV S (in gray, PDB 6CRZ).
Figure 3.
Figure 3.
Entry model of SARS-CoV-2 into the host cell. Binding of the S1 domain within the spike (S) protein to the cellular ACE2 receptor triggers conformational changes in the S2 domain that results in internalization and subsequent membrane fusion ((A) endosomal/clathrin-dependent pathway). The endosomal pathway is facilitated by a low pH and the pH-dependent cysteine protease cathepsin L. Alternatively, SARS-CoV-2 can enter the cell via the nonendosomal/clathrin-independent pathway (B). During this route, ACE2 recognition by the SARS-CoV-2 S protein (comparable to route A) is followed by additional activation/cleavage of the S protein into S1 and S2 domains by cell membrane-associated serine proteases such as TMPRSS2 and TMPRSS11D. The figure was prepared with https://biorender.com/.
Figure 4.
Figure 4.
Genome organization of SARS-CoV-2. Genome organization of the SARS-CoV-2 and location the central genes within the genome (numbers in brackets). The figure was prepared with https://biorender.com/.
Figure 5.
Figure 5.
SARS-CoV-2-RBD and ACE2 interface. ACE2 (in blue) is contacting via its proteolytic domain (PD) with helix α1 the extended loop region (in purple) of SARS-CoV-2 RBD, mainly via polar interactions. In addition, helix α2 and the loop 3–4 connecting β3 and β4 are also contributing to the interface. SARS-CoV-2 S protein monomer was obtained from PDB 6VSB and RBD-ACE2 complex from PDB 6VW1. Boxes 1, 2, and 3 highlight polar clusters 1, 2, and 3, respectively.
Figure 6.
Figure 6.
Structural alignment of the RBD-ACE2 interface from SARS-CoV-2 and SARS-CoV. The SARS-CoV-2 RBD-ACE complex (PDB 6VW1) with ACE2 in blue and RBD in purple/orange are superimposed to the SARS-CoV RBD-ACE complex (PDB 2AJF) with ACE2 in cyan and RBD in green. N-Terminal, central, and C-terminal clusters are highlighted in black boxes with 1, 2, and 3, respectively.
Figure 7.
Figure 7.
Location of synthetic peptides derived from the S1 and S2 domain of the spike protein.
Figure 8.
Figure 8.
Crystal structure of the mature-domain of cathepsin L. The catalytic triad (Cys22, His163, Asn187) essential for proteolytic activity are highlighted in a dashed triangle. N and C represent N- and C-terminus, respectively. PDB 5I4H.
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