Carboxylic Acid Isostere Derivatives of Hydroxypyridinones as Core Scaffolds for Influenza Endonuclease Inhibitors.

Among the most important influenza virus targets is the RNA-dependent RNA polymerase acidic N-terminal (PA _N ) endonuclease, which is a critical component of the viral replication machinery. To inhibit the activity of this metalloenzyme, small-molecule inhibitors employ metal-binding pharmacophores (MBPs) that coordinate to the dinuclear Mn ²⁺ active site. In this study, several metal-binding isosteres (MBIs) were examined where the carboxylic acid moiety of a hydroxypyridinone MBP is replaced with other groups to modulate the physicochemical properties of the compound. MBIs were evaluated for their ability to inhibit PA _N using a FRET-based enzymatic assay, and their mode of binding in PA _N was determined using X-ray crystallography.
Competing Interests: The authors declare the following competing financial interest(s): S.M.C. is a co-founder, has an equity interest, and receives income as member of the Scientific Advisory Board for Forge Therapeutics; is a co-founder, has an equity interest, and is a member of the Scientific Advisory Board for Blacksmith Medicines; and is a co-founder and has an equity interest Cleave Therapeutics (formerly Cleave Biosciences). These companies may potentially benefit from the research results of certain projects in the laboratory of S.M.C. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies.
(© 2022 The Authors. Published by American Chemical Society.)