Carboxylic Acid Isostere Derivatives of Hydroxypyridinones as Core Scaffolds for Influenza Endonuclease Inhibitors.
Stokes RW, Kohlbrand AJ, Seo H, Sankaran B, Karges J, Cohen SM.
Among the most important influenza virus targets is the RNA-dependent RNA polymerase acidic N-terminal (PA<sub>N</sub>) 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<sup>2+</sup> 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<sub>N</sub> using a FRET-based enzymatic assay, and their mode of binding in PA<sub>N</sub> was determined using X-ray crystallography.