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Review
. 2016 Jul 28;59(14):6595-628.
doi: 10.1021/acs.jmedchem.5b01461. Epub 2016 Feb 29.

An Overview of Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy

Thanigaimalai Pillaiyar  1 , Manoj Manickam  2 , Vigneshwaran Namasivayam  1 , Yoshio Hayashi  3 , Sang-Hun Jung  2
Affiliations
Review

An Overview of Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy

Thanigaimalai Pillaiyar et al. J Med Chem. .

Abstract

Severe acute respiratory syndrome (SARS) is caused by a newly emerged coronavirus that infected more than 8000 individuals and resulted in more than 800 (10-15%) fatalities in 2003. The causative agent of SARS has been identified as a novel human coronavirus (SARS-CoV), and its viral protease, SARS-CoV 3CL(pro), has been shown to be essential for replication and has hence been recognized as a potent drug target for SARS infection. Currently, there is no effective treatment for this epidemic despite the intensive research that has been undertaken since 2003 (over 3500 publications). This perspective focuses on the status of various efficacious anti-SARS-CoV 3CL(pro) chemotherapies discovered during the last 12 years (2003-2015) from all sources, including laboratory synthetic methods, natural products, and virtual screening. We describe here mainly peptidomimetic and small molecule inhibitors of SARS-CoV 3CL(pro). Attempts have been made to provide a complete description of the structural features and binding modes of these inhibitors under many conditions.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Schematic representation of the taxonomy of Coronaviridae (according to the International Committee on Taxonomy of Viruses). SARS-CoV belongs to the Betacoronavirus family but has a “b” lineage. *Coronaviridae, along with Arteriviridae, Mesoniviridae, and Roniviridae, are members of this family.
Figure 2
Figure 2
Structure of a coronavirus showing proteins used for replication.
Figure 3
Figure 3
SARS-CoV 3CLpro dimer structure complexed with a substrate-analogue hexapeptidyl CMK inhibitor (PDB ID 1UK4). (A) SARS-CoV 3CLpro dimer structure is presented as ribbons, and inhibitor molecules are shown as ball-and-stick models. Protomer A (the catalytically competent enzyme) is shown in red, protomer B (the inactive enzyme) is shown in blue, and the inhibitor molecules are shown in yellow. The N-finger residues of protomer B are shown in green. The molecular surface of the dimer is superimposed. (B) Cartoon diagram illustrating the important role of the N-finger in both the dimerization and maintenance of the active form of the enzyme is shown. Adapted from Yang, H. et al. (permission Copyright (2003) National Academy of Sciences, U.S.A.
Figure 4
Figure 4
Natural amide substrate hydrolysis by Cys145 and His41 at the active site of 3CLpro.
Figure 5
Figure 5
Chemical structures of inhibitors 1, 2, and 3.
Figure 6
Figure 6
(A) The crystal structure of 1 with TGEV 3CLpro (PDB ID 1P9U) and superimposed 2 with HRV2 3Cpro (PDB ID 1CQQ). The protein binding pocket is shown in surface representation (pink color). The carbon color of compounds 1 (B), 2 (C), and the binding pocket residues of TGEV 3CLpro and HRV2 3Cpro are represented in magenta, green, and dark- and light-gray, respectively. Oxygen atoms are colored in red, nitrogen atoms in blue, sulfur atoms in yellow and hydrogen atoms in white.
Figure 7
Figure 7
Proposed mechanism of cysteine protease inactivation by inhibitors containing Michael acceptor groups.
Figure 8
Figure 8
Structural modifications of compound 2 with a Michael acceptor to produce active compounds 4–15.
Figure 9
Figure 9
Keto-glutamine derivatives with phthalhydrazide (19–27) and thiophene group (28).
Figure 10
Figure 10
Crystal structure of phthalhydrazide-based inhibitor 19 bound to SARS-CoV 3CLpro (PDB ID 2Z3C). The protein binding pocket is shown in surface representation and colored in orange. The carbon atoms of the inhibitor 19 and the binding pocket residues are shown in stick model and colored in green and yellow, respectively. The thiiranium ring formed by amino acid Cys145 is colored in magenta.
Figure 11
Figure 11
Anilide-type peptidomimetics (29–35) and (2S,2S)-aza epoxide (36) and trans-aziridine (37) inhibitors.
Figure 12
Figure 12
Docked pose of 29 (green, stick model) is shown with the binding pocket residues (gray, line model) and interacting residues (orange, stick model) with SARS-CoV 3CLpro (PDB ID 1UK4). The binding pocket of the protein is shown in surface representation and gray in color.
Figure 13
Figure 13
(A) CMK-canonical binding mode with TGEV 3CLpro (PDB code 1P9U), CMK-noncanonical binding mode with active monomer A of SARS CoV 3CLpro (PDB code 1UK4) (B), and (C) the derived inhibitors 38 and 39.
Figure 14
Figure 14
(A) Structure of aldehydes 44 and 45 and (B) substrate based inhibitors 46–48.
Figure 15
Figure 15
Inhibitors with halomethyl ketones and their derivatives 55–60.
Figure 16
Figure 16
Symmetric peptide diols 69–71.
Figure 17
Figure 17
Structural features of etacrynic acids produce their inhibitory activity against SARS-CoV 3CLpro.
Figure 18
Figure 18
Flavonoids and biflavonoid derivatives.
Figure 19
Figure 19
Terpenoid derivatives with inhibitory activity against SARS-CoV 3CLpro.
Figure 20
Figure 20
Sulfone, dihydroimidazole, and N-phenyl-2-(2-pyrimidinylthio)acetamide-type analogues.
Figure 21
Figure 21
Active heterocyclic ester analogues and their inhibitory activities against SARS-CoV 3CLpro.
Figure 22
Figure 22
Mechanism of covalent bond formation of inhibitors 112 and 120 with the active site cysteine residue of SARS-CoV 3CLpro.
Figure 23
Figure 23
Active 5-chloropyridine ester analogues and their inhibitory activity against SARS 3CLpro.
Figure 24
Figure 24
Halomethyl pyridyl ketones and their inhibition potential against SARS-CoV 3CLpro.
Figure 25
Figure 25
Pyrazolones and pyrimidines and their inhibition potential against SARS-CoV 3CLpro.
Figure 26
Figure 26
Novel decahydroisoquinoline derivatives as SARS-CoV 3CLpro inhibitors.
Figure 27
Figure 27
Primary SAR study at hit furyl amide 145 and schematic representation of enzyme pockets occupied by 146 and 11.
Figure 28
Figure 28
X-ray crystal structure of 146 bound to the binding pocket SARS-CoV 3CLpro (PDB ID 3V3M). The pockets S1′–S3 are highlighted, and the compound 146 is represented in stick model and colored in cyan.
Figure 29
Figure 29
SAR studies at the P1′ (A) and P1 sites (B) of 146 and chiral separation of 146-(R,S) (C) to 146-(R) and 146-(S) enantiomers.
Figure 30
Figure 30
(A) SAR studies at the P1, (B) P2–P1′, and (C) P3-truncation of hit 157 to inhibitors (158–167).
Figure 31
Figure 31
X-ray crystal structure of 157 bound to SARS-CoV 3CLpro (PDB ID: 4MDS) is represented in surface model. The compound 157 (green) is shown in stick model, and the interacting residues (magenta) and the binding pocket residues (gray) are shown in line model.
Figure 32
Figure 32
Profiles of SARS-CoV 3CLpro inhibitors 146-(R), 160, and 165.
Figure 33
Figure 33
Metal-conjugated inhibitors and their inhibition potential against SARS-CoV 3CLpro.
Figure 34
Figure 34
Miscellaneous SAR–CoV 3CLpro inhibitors.
Figure 35
Figure 35
Profile of representative peptidic SARS-CoV 3CLpro inhibitors highlighting reactive warhead groups (red).
Figure 36
Figure 36
Profile of representative nonpeptidic SARS-CoV 3CLpro inhibitors highlighting reactive warhead groups (red).
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