Exploration of the P1 residue in 3CL protease inhibitors leading to the discovery of a 2-tetrahydrofuran P1 replacement

Bioorg Med Chem. 2024 Jan 29;100:117618. doi: 10.1016/j.bmc.2024.117618. Online ahead of print.ABSTRACTThe virally encoded 3C-like protease (3CLpro) is a well-validated drug target for the inhibition of coronaviruses including Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Most inhibitors of 3CLpro are peptidomimetic, with a γ-lactam in place of Gln at the P1 position of the pseudopeptide chain. An effort was pursued to identify a viable alternative to the γ-lactam P1 mimetic which would improve physicochemical properties while retaining affinity for the target. Discovery of a 2-tetrahydrofuran as a suitable P1 replacement that is a potent enzymatic inhibitor of 3CLpro in SARS-CoV-2 virus is described herein.PMID:38309201 | DOI:10.1016/j.bmc.2024.117618

Source: Bioorganic and Medicinal Chemistry - February 3, 2024 Category: Chemistry Authors: Linda S Barton James F Callahan Juan Cantizani Nestor O Concha Ignacio Cotillo Torrejon Nicole C Goodwin Amruta Joshi-Pangu Terry J Kiesow Jeff J McAtee Mark Mellinger Christopher J Nixon Laura Padr ón-Barthe Jaclyn R Patterson Neil D Pearson Jeffrey J P Source Type: research