The SARS‐CoV‐2 main protease (M^pro): Structure, function, and emerging therapies for COVID‐19

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.

Chemo- and Site-Selective Lysine Modification of Peptides and Proteins under Native Conditions Using the Water-Soluble Zolinium

“…The potential applications of the zoliniums and their derivatives in drug discovery were demonstrated via targeting the SARS-CoV-2 3CL protease, an essential enzyme for virus replication in host cells. , It was found that 5B could inhibit SARS-CoV-2 3CL pro in a dose- and time-dependent manner, with an IC 50 value as low as 3.66 μM following a long preincubation time (60 min). By contrast, the IC 50 value of 5B against 3CL pro was 75.01 μM without a long preincubation time (Figure e and Figure S7).…”

Gold-Based Metal Drugs as Inhibitors of Coronavirus Proteins: The Inhibition of SARS-CoV-2 Main Protease by Auranofin and Its Analogs

“…Each monomer contains three domains. More in detail, domain I (residues 8–101) and domain II (102–184) fold in an antiparallel β-barrel -where the active site with the Cys145-His41 catalytic dyad is located [ 7 ] whereas domain III (residues 201–306) is involved in the process of dimerization that is critical for the function of the enzyme [ 8 ]. The two subunits of M pro bind to each other via the N-terminus (residues 1–7) where the Ser1 of each monomer completes and stabilizes the S1 substrate binding pocket of the adjacent monomer [ 9 ].…”

Drugs for COVID-19: An Update

“…These are summarized in Table 2 . Some clinical advances in the development of small-molecule drugs targeting SARS-CoV-2 3CL pro have been reported by Hu et al [ 91 ]. The noncovalent, reversible oral nonpeptidic SARS-CoV-2 3CL protease inhibitor clinical candidate, namely S-217622 developed by Shionogi, has been deeply studied [ 92 ].…”