7R7H

Peptidomimetic nitrile warheads as SARS-CoV-2 3CL protease inhibitors

Summary for 7R7H

• Entry DOI: 10.2210/pdb7r7h/pdb
• Descriptor: 3C-like proteinase, N-[(2S)-1-({(1E,2S)-1-imino-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}amino)-4-methyl-1-oxopentan-2-yl]-4-methoxy-1H-indole-2-carboxamide (3 entities in total)
• Functional Keywords: viral protein, hydrolase-hydrolase inhibitor complex, hydrolase
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• Total number of polymer chains: 2
• Total formula weight: 68534.14

Authors

Khan, M.B.,Lu, J.,Young, H.S.,Lemieux, M.J. (deposition date: 2021-06-24, release date: 2021-09-01, Last modification date: 2024-11-13)

Primary citation

Bai, B.,Arutyunova, E.,Khan, M.B.,Lu, J.,Joyce, M.A.,Saffran, H.A.,Shields, J.A.,Kandadai, A.S.,Belovodskiy, A.,Hena, M.,Vuong, W.,Lamer, T.,Young, H.S.,Vederas, J.C.,Tyrrell, D.L.,Lemieux, M.J.,Nieman, J.A.
Peptidomimetic nitrile warheads as SARS-CoV-2 3CL protease inhibitors.
Rsc Med Chem, 12:1722-1730, 2021

PubMed Abstract: Tragically, the death toll from the COVID-19 pandemic continues to rise, and with variants being observed around the globe new therapeutics, particularly direct-acting antivirals that are easily administered, are desperately needed. Studies targeting the SARS-CoV-2 3CL protease, which is critical for viral replication, with different peptidomimetics and warheads is an active area of research for development of potential drugs. To date, however, only a few publications have evaluated the nitrile warhead as a viral 3CL protease inhibitor, with only modest activity reported. This article describes our investigation of P3 4-methoxyindole peptidomimetic analogs with select P1 and P2 groups with a nitrile warhead that are potent inhibitors of SARS-CoV-2 3CL protease and demonstrate 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.

PubMed: 34778773
DOI: 10.1039/d1md00247c

Experimental method

X-RAY DIFFRACTION (2.15 Å)