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 (FBDD) campaign was pursued. Guided by coordination chemistry and structure-based drug design (SBDD), MBP scaffolds were elaborated to improve activity and selectivity. Structure-activity relationships (SARs) were established and used to generate inhibitors of influenza endonuclease with tight binding affinities. The activity of these inhib- itors was analyzed using a fluorescence quenching-based nuclease activity assay and binding was validated using differential scanning fluo- rometry (DSF). 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 t...