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. 2023 Jan 19;15(2):287.
doi: 10.3390/v15020287.

Quinazolinone-Peptido-Nitrophenyl-Derivatives as Potential Inhibitors of SARS-CoV-2 Main Protease

Huynh-Nguyet-Huong Giang  1 , Feng-Pai Chou  2   3 , Ching-Yun Chen  2 , Shen-Chieh Chou  2 , Sheng-Cih Huang  2 , Tuoh Wu  2 , Bui-Thi-Buu Hue  4 , Hong-Cheu Lin  1   3 , Tung-Kung Wu  2   3
Affiliations

Quinazolinone-Peptido-Nitrophenyl-Derivatives as Potential Inhibitors of SARS-CoV-2 Main Protease

Huynh-Nguyet-Huong Giang et al. Viruses. .

Abstract

The severe acute respiratory syndrome coronavirus 2 main protease (SARS-CoV-2-Mpro) plays an essential role in viral replication, transcription, maturation, and entry into host cells. Furthermore, its cleavage specificity for viruses, but not humans, makes it a promising drug target for the treatment of coronavirus disease 2019 (COVID-19). In this study, a fragment-based strategy including potential antiviral quinazolinone moiety and glutamine- or glutamate-derived peptidomimetic backbone and positioned nitro functional groups was used to synthesize putative Mpro inhibitors. Two compounds, G1 and G4, exhibited anti-Mpro enzymatic activity in a dose-dependent manner, with the calculated IC50 values of 22.47 ± 8.93 μM and 24.04 ± 0.67 μM, respectively. The bio-layer interferometer measured real-time binding. The dissociation kinetics of G1/Mpro and G4/Mpro also showed similar equilibrium dissociation constants (KD) of 2.60 × 10-5 M and 2.55 × 10-5 M, respectively, but exhibited distinct association/dissociation curves. Molecular docking of the two compounds revealed a similar binding cavity to the well-known Mpro inhibitor GC376, supporting a structure-function relationship. These findings may open a new avenue for developing new scaffolds for Mpro inhibition and advance anti-coronavirus drug research.

Keywords: SARS-CoV-2; main protease Mpro; peptidomimetic; quinazolinone; targeted covalent inhibitor.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Schematic presentation of the SARS-CoV-2 genome organization. (A) Full-length genomic RNA (29,903 nt) that serves as an mRNA, containing ORF1a, ORF1b, and nine subgenomic RNAs. (B) Schematic representation of non-structural polyprotein cleavage sites. There are two viral proteases: a papain-like protease (PLpro) cleaves virus nonstructural polyprotein at three sites, and the other main protease (Mpro) recognizes and cleaves the virus non-structural polyprotein at 11 sites.
Figure 2
Figure 2
Synthesis of fragment-based compounds containing glutamine- or glutamic acid-derived peptidomimetic backbone, quinazolinone moiety, and nitro-functionalized phenyl derivatives.
Figure 3
Figure 3
Inhibitory activity of serial dilutions of G1 (A) and G4 (B) against SARS-CoV-2 Mpro.
Figure 4
Figure 4
Bio-layer interferometry analysis of G1 and G4 with Mpro. (A) Association and dissociation data of G1 with Mpro. (B) Association and dissociation data of G4 with Mpro.
Figure 5
Figure 5
Molecular docking of GC376 and SARS-CoV-2 Mpro. (A) 3D interactions between GC376 (Cyan) and Mpro (Green). (B) 2D interactions, including H-bonding, hydrophobic, π−sulfur, π−π, and π−alkyl interactions between GC376 and Mpro, identified by Discovery Studio.
Figure 6
Figure 6
Molecular docking of G1 and SARS-CoV-2 Mpro. (A) 3D interaction between G1 (cyan) and Mpro (green). (B) 2D interactions between G1 and Mpro, including H-bonding, hydrophobic, π−sulfur, π−π, and π−alkyl interactions, as determined by Discovery Studio.
Figure 7
Figure 7
Molecular docking of G4 and SARS-CoV-2 Mpro. (A) 3D H-bond interactions between G4 (cyan) and Mpro (green). (B) 2D interactions between G4 and Mpro, including H-bond, hydrophobic, π−sulfur, and π−π interactions, as determined by Discovery Studio.
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