Biological and Medicinal Chemistry

Design, Synthesis and Biological Evaluation of Novel SARS-CoV-2 3CLpro Covalent Inhibitors

Abstract

Severe diseases such as the ongoing COVID-19 pandemic, as well as the previous SARS and MERS outbreaks, are the result of coronavirus infections and have demonstrated the urgent need for antiviral drugs to combat these deadly viruses. Due to its essential role in viral replication and function, 3CLpro> has been identified as a promising target for the development of antiviral drugs. Previously reported SARS-CoV 3CLpro non-covalent inhibitors were used as a starting point for the development of covalent inhibitors of SARS-CoV-2 3CLpro. We report herein our efforts in design and synthesis which led to submicromolar covalent inhibitors when the enzymatic activity of the viral protease was used as a screening platform.

Version notes

Additional compounds were made and tested, Crystallography enabled the confirmation of the binding mode and additiona kinetics studies provided essential information on these covalent inhibitors.

Content

Thumbnail image of Moitessier-Mittermaier ChemRXiv- 3CLpro inhibitors v3.pdf

Supplementary material

Thumbnail image of Moitessier-Mittermaier - 3CLpro inhibitors - SuppInf.pdf
Moitessier-Mittermaier - 3CLpro inhibitors - SuppInf
Experimental data and additional information.