Peptidomimetic nitrile warheads as SARS-CoV-2 3CL protease inhibitors
Bing Bai, Elena Arutyunova, Muhammad Bashir Khan, Jimmy Lu, Michael Joyce, Holly A. Saffran, Justin Shields, Appan Srinivas Kandadai, Alexandr Belovodskiy, Mostofa Abu Hena, Wayne Vuong, Tess Lamer, Howard S. Young, John C. Vederas, D. Lorne Tyrrell, M. Joanne Lemieux, James A. Nieman
Abstract
SARS-CoV-2 antiviral activity. A selectivity for SARS-CoV-2 3CL protease over human cathepsins B, S and L was also observed with the nitrile warhead, which was superior to that with the aldehyde warhead. A co-crystal structure with SARS-CoV-2 3CL protease and a reversibility study indicate that a reversible, thioimidate adduct is formed when the catalytic sulfur forms a covalent bond with the carbon of the nitrile. This effort also identified efflux as a property limiting antiviral activity of these compounds, and together with the positive attributes described these results provide insight for further drug development of novel nitrile peptidomimetics targeting SARS-CoV-2 3CL protease.