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Review
. 2023 Sep 5:257:115491.
doi: 10.1016/j.ejmech.2023.115491. Epub 2023 May 22.

The research progress of SARS-CoV-2 main protease inhibitors from 2020 to 2022

Xiaojing Pang  1 , Wei Xu  2 , Yang Liu  1 , Hua Li  3 , Lixia Chen  4
Affiliations
Review

The research progress of SARS-CoV-2 main protease inhibitors from 2020 to 2022

Xiaojing Pang et al. Eur J Med Chem. .

Abstract

The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide. The main protease (Mpro) of SARS-CoV-2 plays a central role in viral replication and transcription and represents an attractive drug target for fighting COVID-19. Many SARS-CoV-2 Mpro inhibitors have been reported, including covalent and noncovalent inhibitors. The SARS-CoV-2 Mpro inhibitor PF-07321332 (Nirmatrelvir) designed by Pfizer has been put on the market. This paper briefly introduces the structural characteristics of SARS-CoV-2 Mpro and summarizes the research progress of SARS-CoV-2 Mpro inhibitors from the aspects of drug repurposing and drug design. These information will provide a basis for the drug development of treating the infection of SARS-CoV-2 and even other coronaviruses in the future.

Keywords: COVID-19; Drug design; Drug repurposing; M(pro) inhibitors; SARS-CoV-2.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
Schematic representation of the taxonomy of Coronaviruses.
Fig. 2
Fig. 2
Structure and function of SARS-CoV-2 Mpro. (A) The structure of coronavirus. (B) Coronavirus (SARS-CoV-2) genome. (C) Overall scheme of natural amide substrate hydrolysis by Cys145 and His41 at the active site of Mpro: a. The first step in the process is the deprotonation of the Cys145-thiol; b. In the second step, the anionic sulfur next attacks the substrate carbonyl carbon; c. Then, the product with an amino terminus is released, while the His41 is restored its deprotonated form; d. Next, the generated thioester is hydrolyzed to release the carboxylic acid. e. In the last step, the Cys-His catalytic binary is formed again for the next proteolytic cycle.
Fig. 3
Fig. 3
Approved and clinical drugs of SARS-CoV-2.
Fig. 4
Fig. 4
Structures and biological activity data of derivatives 53–58 of PF-07321332 and Ebselen.
Fig. 5
Fig. 5
Structures and biological activity data of derivatives 59–66 of GC-376.
Fig. 6
Fig. 6
Structures and biological activity data of compounds 67–70.
Fig. 7
Fig. 7
Structures and biological activity data of derivatives 3, 21 and 71–77 of PF-00835231.
Fig. 8
Fig. 8
The structures of compounds 78–80 and the crystal structure docking diagram with SARS-CoV-2 Mpro (PDB ID: 7RC0).
Fig. 9
Fig. 9
Structures and biological activity data of compounds 81–98.
Fig. 10
Fig. 10
Structures and biological activity data of compounds 99–108.
Fig. 11
Fig. 11
Discovery of SARS-CoV-2 Mpro inhibitors assisted by drug repurposing.
Fig. 12
Fig. 12
The most common fragment in P1', P1, P2, P3.
See this image and copyright information in PMC

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