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

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 (M^pro) 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 M^pro inhibitors have been reported, including covalent and noncovalent inhibitors. The SARS-CoV-2 M^pro inhibitor PF-07321332 (Nirmatrelvir) designed by Pfizer has been put on the market. This paper briefly introduces the structural characteristics of SARS-CoV-2 M^pro and summarizes the research progress of SARS-CoV-2 M^pro 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.

Graphical abstract

Fig. 1

Schematic representation of the taxonomy of Coronaviruses.

Fig. 2

Structure and function of SARS-CoV-2 M^pro. (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 M^pro: 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

Approved and clinical drugs of SARS-CoV-2.

Fig. 4

Structures and biological activity data of derivatives 53–58 of PF-07321332 and Ebselen.

Fig. 5

Structures and biological activity data of derivatives 59–66 of GC-376.

Fig. 6

Structures and biological activity data of compounds 67–70.

Fig. 7

Structures and biological activity data of derivatives 3, 21 and 71–77 of PF-00835231.

Fig. 8

The structures of compounds 78–80 and the crystal structure docking diagram with SARS-CoV-2 M^pro (PDB ID: 7RC0).

Fig. 9

Structures and biological activity data of compounds 81–98.

Fig. 10

Structures and biological activity data of compounds 99–108.

Fig. 11

Discovery of SARS-CoV-2 M^pro inhibitors assisted by drug repurposing.

Fig. 12

The most common fragment in P1', P1, P2, P3.