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

Abstract

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.

Iminodiacetic Acid as a Novel Metal‐Binding Pharmacophore for New Delhi Metallo‐β‐lactamase Inhibitor Development

“…In contrast, the removal of Zn II has been observed to destabilize the protein and results in a negative Δ T m (as seen with DPA) . It is important to note that while reported thermal shift data have revealed a good correlation between the observed IC 50 value and ▵ T m , this correlation has not been observed for inhibitors of NDM‐1 . In the case of the compounds tested here, ▵ T m did not correlate with IC 50 values.…”

Expanding medicinal chemistry into 3D space: metallofragments as 3D scaffolds for fragment-based drug discovery

“…47,48 The role of these enzymes in their respective diseases and inhibitor development for each are presented elsewhere. [47][48][49] Briey, PA N endonuclease is one of three proteins in the RNAdependent RNA polymerase complex of the inuenza A virus, along with the polymerase basic protein 1 (PB1) and the polymerase basic protein 2 (PB2). 50 PA N endonuclease contains a dinuclear metal active site, with two Mn 2+ or Mg 2+ cations that promote endonuclease activity.…”

Effect of heterocycle content on metal binding isostere coordination

“…Efforts to apply fragment-based drug discovery (FBDD) to metalloenzymes has produced new libraries of potential MBPs. [3][4][5] However, some new MBPs may possess physiochemical properties that limit their viability for use in drug candidates. 6,7 In medicinal chemistry, functional groups that adversely modulate the pharmacological properties of a drug candidate or introduce clear pharmacological liabilities are oen replaced with alternate functional groups with broadly similar properties referred to as bioisosteres.…”