Progress in Research on Inhibitors Targeting SARS-CoV-2 Main Protease (Mpro)

Abstract

Since 2019, the novel coronavirus (SARS-CoV-2) has caused significant morbidity and millions of deaths worldwide. The Coronavirus Disease 2019 (COVID-19), caused by SARS-CoV-2 and its variants, has further highlighted the urgent need for the development of effective therapeutic agents. Currently, the highly conserved and broad-spectrum nature of main proteases (M^pro) renders them of great importance in the field of inhibitor study. In this study, we categorize inhibitors targeting M^pro into three major groups: mimetic, nonmimetic, and natural inhibitors. We then present the research progress of these inhibitors in detail, including their mechanism of action, antiviral activity, pharmacokinetic properties, animal experiments, and clinical studies. This review aims to provide valuable insights and potential avenues for the development of more effective antiviral drugs against SARS-CoV-2.

Figure 1

Coronavirus particles are composed of four structural proteins, namely, S protein, E protein, M protein, and N protein. S, M, and E are doped into the viral particle when the RNA genome is wrapped in N. Coronavirus particles bind to cell attachment factors, facilitating their uptake and fusion in cell membranes or endosomal membranes. Upon entry, the RNA genome is released, decapsulated, and immediately translated by ORF1a and ORF1b. The resulting polyproteins, pp1a and pp1ab, undergo cotranslation and post-translational processing into individual nonstructural proteins (nsps) that form the viral replication and transcription complex (RTC). Then RTC replicates the viral genome to the negatively stranded genomic RNA. Translated E and M facilitate virus assembly and budding by interacting with other viral proteins. Viruses budding into the ERGIC lumen reach the plasma membrane by secretion, and virus-containing vesicles are released outside the cell after fusion with the plasma membrane.

Figure 2

Crystal structure of M^pro (A) (PBD ID: 7BB2). The structural region of M^pro (B) (PBD ID: 7ALH). The cavity structure of M^pro (C).

Figure 3

Molecular structure (A) and crystal structure (E) of RAY1216 (PBD ID: 8IGN). The molecular structures of SY110 (B) and MK-7845 (C) (red color indicates the modified moiety at P1). The optimization process from 11r to 13b (D) and crystal structure of 13b (F) (PBD ID: 6Y2F) (C) (Represent the evolution of 13b in turn in red, green, purple, and blue.) (All structural formulas were drawn in ChemDraw; 3D representations were drawn in Pymol.)

Figure 4

Molecular structures of 9a and 9e (A); the molecular structures of CMX990 (B) and BBH-1 (C); the molecular structures of PF-07304814 and PF-00835231 (D); the molecular structure (G) and crystal structure (E) of 11a (PBD: 6LZE); and the molecular structures of MI-09 and MI-30 (F).

Figure 5

Molecular structure (A) and crystal structure (C) of 10a (PBD: 7DHJ). The molecular structures of TPM16 (B). The molecular structure (D) and crystal structure (G) of YH-6 (PBD: 7XAR). The molecular structure of D-4-77 (E) and MPI89 (F) (the warheads of YH-6, D-4-77, and MPI89 are marked in red). The molecular structure of GC376 (H) and NK01-63 (I).

Figure 6

Molecular structure of Nirmatrelvir and its base structure (A) (different colors mark the main variations of the compounds). The crystal structure of Nirmatrelvir (D) (PBD: 7RFS). The molecular structure of Simnotrelvir (B) (nitrile groups are shown in green). The molecular structure of BBH series (C).

Figure 7

Molecular structure of UCI-1 (A), Cyclic peptide 1 (B), GM4 (C) (the ring-forming portion is shown in red), Compound 15 and Compound 16 (D), and 7d, 8e, and 9g (E).

Figure 8

Molecular structure of 1i and 2k (A), metal complexes (B), Y180 (C), Jun9-62-2R (D), CD-19 (E), 6a and 3a (F), 16a and 14a (G), and GRL-0820 and GRL-0920 (H).

Figure 9

Molecular structures (A) and crystal structure (G) of S-217622 (PBD: 7VU6). The molecular structure of WU-04 (B). The molecular structure (C) and crystal structure (H) of Masitinib (PBD: 7JU7). The molecular structure of MAT-POS-e194df51-1 (D). The molecular structure (E) and crystal structure (F) of LY1 (PBD: 7V1T) (the differences between the two forms of LY1 are marked in red).

Figure 10

Molecular structure of ML188 (A). The molecular structure (B) and crystal structure (C) of 23R (PBD: 7KX5). The molecular structure of X77 (D), GC-14 (E), C1, C2 (F), C7 (G), C5 and C5a (H) (differences between the two molecules are marked in red), and Compound 19 (I).

Figure 11

Molecular structure of Hypericum perforatum (A), PGG and EGCG (B), Pentarlandir UPPTA (C), and Win and WifA (D).

Figure 12

Molecular structure of Emetine (A), Baicalin and Baicalin (B), Compound 15 (C), OVA (D), Compound 15 (E), and Eupatin (F).