Design, synthesis and in vitro evaluation of novel SARS-CoV-2 3CLpro covalent inhibitors.

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 (main coronaviruses cysteine-protease) 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 the design and synthesis of submicromolar covalent inhibitors when the enzymatic activity of the viral protease was used as a screening platform. [Display omitted] • Covalent docking was used to design SARS-CoV-2 3CLpro inhibitors. • A micromolar non-covalent SARS-CoV 3CLpro inhibitor was converted into a submicromolar SARS-CoV-2 3CLpro covalent inhibitor. • A set of warheads was evaluated and vinyl sulfonamide and alkynylamide were identified as promising warheads. • Crystallography confirmed the docking-proposed mode of binding. • SAR studies led to improved potency. [ABSTRACT FROM AUTHOR]