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 (PAN) 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
Mn2+ 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 PAN using a FRET-based enzymatic
assay, and their mode of binding in PAN was determined
using X-ray crystallography.