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Review
. 2020 Aug 27;25(17):3920.
doi: 10.3390/molecules25173920.

Design and Evaluation of Anti-SARS-Coronavirus Agents Based on Molecular Interactions with the Viral Protease

Kenichi Akaji  1 , Hiroyuki Konno  2
Affiliations
Review

Design and Evaluation of Anti-SARS-Coronavirus Agents Based on Molecular Interactions with the Viral Protease

Kenichi Akaji et al. Molecules. .

Abstract

Three types of new coronaviruses (CoVs) have been identified recently as the causative viruses for the severe pneumonia-like respiratory illnesses, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and corona-virus disease 2019 (COVID-19). Neither therapeutic agents nor vaccines have been developed to date, which is a major drawback in controlling the present global pandemic of COVID-19 caused by SARS coronavirus 2 (SARS-CoV-2) and has resulted in more than 20,439,814 cases and 744,385 deaths. Each of the 3C-like (3CL) proteases of the three CoVs is essential for the proliferation of the CoVs, and an inhibitor of the 3CL protease (3CLpro) is thought to be an ideal therapeutic agent against SARS, MERS, or COVID-19. Among these, SARS-CoV is the first corona-virus isolated and has been studied in detail since the first pandemic in 2003. This article briefly reviews a series of studies on SARS-CoV, focusing on the development of inhibitors for the SARS-CoV 3CLpro based on molecular interactions with the 3CL protease. Our recent approach, based on the structure-based rational design of a novel scaffold for SARS-CoV 3CLpro inhibitor, is also included. The achievements summarized in this short review would be useful for the design of a variety of novel inhibitors for corona-viruses, including SARS-CoV-2.

Keywords: Corona-virus; SARS; inhibitor; protease.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(a) Crystal structure of SARS-CoV 3CLpro active dimer (PDB code 1Q2W). (b) Structure of the active center.
Figure 2
Figure 2
Hydrolysis of the substrate by thiol protease.
Figure 3
Figure 3
Inhibition of cysteine proteases by a Michael acceptor type compound.
Figure 4
Figure 4
A possible mechanism for the inactivation by a halomethyl ketone inhibitor.
Figure 5
Figure 5
Proposed mechanism of inhibition by a trifluoromethyl ketone compound.
Figure 6
Figure 6
Inhibition with peptides having thiazolyl ketone warhead.
Figure 7
Figure 7
Structures and IC50 values of the nitrile-based inhibitors against SARS-CoV 3CLpro.
Figure 8
Figure 8
Interactions of the nitrile-based inhibitor with SARS-CoV 3CLpro.
Figure 9
Figure 9
Nucleophilic addition reaction to peptide aldehydes.
Figure 10
Figure 10
Structures of peptide aldehydes 30 and 31.
Figure 11
Figure 11
Interactions of inhibitor 37 with R188I SARS-CoV 3CLpro.
Figure 12
Figure 12
Design of the serine derivative as a nonpeptide inhibitor for SARS-CoV 3CLpro.
Figure 13
Figure 13
Design of a decahydroisoquinoline scaffold.
Figure 14
Figure 14
Interactions of inhibitor 42 at the active center (a) and P2 site (b) of SARS-CoV 3CLpro.
Figure 15
Figure 15
Comparison of the X-ray crystal structure of SARS-CoV 3CLpro complexed with decahydroisoquinoline-type inhibitor 42 (PDB code 4TWW) and the peptide aldehyde inhibitor 37 (PDB code 3ATW).
Figure 16
Figure 16
Design of a novel prototype nonpeptide inhibitor.
See this image and copyright information in PMC

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