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Review
. 2022 Jul 14;3(3):e151.
doi: 10.1002/mco2.151. eCollection 2022 Sep.

The SARS-CoV-2 main protease (Mpro): Structure, function, and emerging therapies for COVID-19

Qing Hu  1   2 , Yuan Xiong  1 , Guang-Hao Zhu  1 , Ya-Ni Zhang  1 , Yi-Wen Zhang  2 , Ping Huang  2 , Guang-Bo Ge  1
Affiliations
Review

The SARS-CoV-2 main protease (Mpro): Structure, function, and emerging therapies for COVID-19

Qing Hu et al. MedComm (2020). .

Abstract

The main proteases (Mpro), also termed 3-chymotrypsin-like proteases (3CLpro), are a class of highly conserved cysteine hydrolases in β-coronaviruses. Increasing evidence has demonstrated that 3CLpros play an indispensable role in viral replication and have been recognized as key targets for preventing and treating coronavirus-caused infectious diseases, including COVID-19. This review is focused on the structural features and biological function of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease Mpro (also known as 3CLpro), as well as recent advances in discovering and developing SARS-CoV-2 3CLpro inhibitors. To better understand the characteristics of SARS-CoV-2 3CLpro inhibitors, the inhibition activities, inhibitory mechanisms, and key structural features of various 3CLpro inhibitors (including marketed drugs, peptidomimetic, and non-peptidomimetic synthetic compounds, as well as natural compounds and their derivatives) are summarized comprehensively. Meanwhile, the challenges in this field are highlighted, while future directions for designing and developing efficacious 3CLpro inhibitors as novel anti-coronavirus therapies are also proposed. Collectively, all information and knowledge presented here are very helpful for understanding the structural features and inhibitory mechanisms of SARS-CoV-2 3CLpro inhibitors, which offers new insights or inspiration to medicinal chemists for designing and developing more efficacious 3CLpro inhibitors as novel anti-coronavirus agents.

Keywords: 3‐chymotrypsin‐like protease (3CLpro); SARS‐CoV‐2; broad‐spectrum anti‐coronavirus agents; β‐coronavirus 3CLpro inhibitor.

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Conflict of interest statement

The authors declare they have no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Phylogenetic relationships for 14 reported 3‐chymotrypsin‐like proteases (3CLpros) in Nidovirus. (A) The evolutionary distances (genetic variations) of 3CLpros are presented on branches. (B) Amino acid homologous sequence alignment of 3CLpros
FIGURE 2
FIGURE 2
(A) The 3D structure of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) 3CLpro (pale green, PDB: 6XHU) and severe acute respiratory syndrome coronavirus (SARS‐CoV) 3CLpro (slate, PDB: 1UJ1). (B) Three structural domains (domain I: orange, domain II: yellow, domain III: blue) of SARS‐CoV‐2 3CLpro monomer. (C) The surface representation for the catalytic pocket (sub‐pockets: S1–S5) of SARS‐CoV‐2 3CLpro. (D) The amino acid residues in the active site of SARS‐CoV‐2 3CLpro. (E) The catalytic mechanism of 3CLpro on the hydrolysis of amide substrate
FIGURE 3
FIGURE 3
The chemical structures and half‐maximal inhibitory concentration (IC50) values for representative peptidomimetic SARS‐CoV‐2 3CLpro inhibitors, as well as their half‐maximal effect concentration (EC50) values for anti‐SARS‐CoV‐2
FIGURE 4
FIGURE 4
The structures and half‐maximal inhibitory concentration (IC50) values for representative non‐peptidomimetic SARS‐CoV‐2 3CLpro inhibitors, as well as their half‐maximal effect concentration (EC50) values for anti‐SARS‐CoV‐2
FIGURE 5
FIGURE 5
The structures and half‐maximal inhibitory concentration (IC50) values for representative naturally derived SARS‐CoV‐2 3CLpro inhibitors
FIGURE 6
FIGURE 6
The structures and half‐maximal inhibitory concentration (IC50) values for representative clinical candidates SARS‐CoV‐2 3CLpro inhibitors, as well as their half‐maximal effect concentration (EC50) values for anti‐SARS‐CoV‐2
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