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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]

Over the past decade, many drug discovery endeavors have been invested in targeting the serine proteases prolyl oligopeptidase (POP) for the treatment of Alzheimer's and Parkinson's disease and, more recently, epithelial cancers. Our research group has focused on the discovery of reversible covalent inhibitors, namely nitriles, to target the catalytic serine residue in this enzyme. While there have been many inhibitors discovered containing a nitrile to covalently bind to the catalytic serine, we have been investigating others, particularly boronic acids and boronic esters, the latter of which have been largely unexplored as covalent warheads. Herein we report a series of computationally-designed POP boronic ester pro-drug inhibitors exhibiting nanomolar-potencies in vitro as their active boronic acid species. These easily-accessible (1–2 step syntheses) compounds could facilitate future biochemical and biological studies of this enzyme's role in neurodegenerative diseases and cancer progression. Image 1 • Potent covalent POP inhibitors were developed. • Boronic esters are acting as pro-drugs. • Computational design successfully led to potent inhibitors. • A scalable synthesis was devised. [ABSTRACT FROM AUTHOR]