SAR Exploration of Tight-Binding Inhibitors of Influenza Virus PA Endonuclease

Significant efforts
have been reported on the development of influenza
antivirals including inhibitors of the RNA-dependent RNA polymerase
PA N-terminal (PAN) endonuclease. Based on recently identified,
highly active metal-binding pharmacophores (MBPs) for PAN endonuclease inhibition, a fragment-based drug development campaign
was pursued. Guided by coordination chemistry and structure-based
drug design, MBP scaffolds were elaborated to improve activity and
selectivity. Structure–activity relationships were established
and used to generate inhibitors of influenza endonuclease with tight-binding
affinities. The activity of these inhibitors was analyzed using a
fluorescence-quenching-based nuclease activity assay, and binding
was validated using differential scanning fluorometry. Lead compounds
were found to be highly selective for PAN endonuclease
against several related dinuclear and mononuclear metalloenzymes.
Combining principles of bioinorganic and medicinal chemistry in this
study has resulted in some of the most active in vitro influenza PAN endonuclease inhibitors with high ligand efficiencies.