Design and synthesis of naturally-inspired SARS-CoV-2 inhibitors - Biologie des ARN et virus influenza - RNA Biology of Influenza Virus Access content directly
Journal Articles RSC Medicinal Chemistry Year : 2023

Design and synthesis of naturally-inspired SARS-CoV-2 inhibitors

Afnan Hassan
Loay Bedda
Alice Shi Ming Li
Adrien Delpal
Masoud Vedadi
Reem Arafa

Abstract

A naturally inspired chemical library of 25 molecules was synthesised guided by 3-D dimensionality and natural product likeness factors to explore a new chemical space. The synthesised chemical library, consisting of fused- bridged dodecahydro-2a,6-epoxyazepino[3,4,5-cd] indole skeletons, followed lead likeness factors in terms of molecular weight, C-sp3 fraction and CLogP. Screening of the 25 compounds against lung cells infected with SARS- CoV-2 led to the identification of 2 hits. Although the chemical library showed cytotoxicity, the two hits (3b, 9e) showed the highest antiviral activity (EC50 values of 3.7 and 1.4 μM, respectively) with acceptable cytotoxicity difference. Computational analysis based on docking and molecular dynamics simulations against main protein targets in SARS-CoV-2 (Main Protease Mpro, Nucleocapsid phosphoprotein, Non-structural protein nsp10/nsp16 complex and RBD/ACE2 complex) were performed. The computational analysis proposed the possible binding targets to be either Mpro or nsp10/nsp16 complex. Biological assasys were performed to confirm this propostion. A cell-based assay for Mpro protease activity using a Reverse-Nanoluciferase (Rev-Nluc) reporter confirmed that 3b is targeting Mpro. These results open the way towards further hit-to-lead optimisations.
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Dates and versions

hal-03981817 , version 1 (06-11-2023)

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Haitham Hassan, Jeanne Chiavaralli, Afnan Hassan, Loay Bedda, Tim Krischuns, et al.. Design and synthesis of naturally-inspired SARS-CoV-2 inhibitors. RSC Medicinal Chemistry, 2023, 14 (3), pp.507-519. ⟨10.1039/D2MD00149G⟩. ⟨hal-03981817⟩
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