Allosteric pockets in the measles and Nipah virus polymerases: Mechanobiological insights and AI-driven drug discovery opportunities

Abstract

Nonsegmented negative-sense RNA viruses (nsNSVs)—including highly pathogenic pathogens such as measles virus (MeV), Nipah virus (NiV), Hendra virus (HeV), Ebola virus (EBOV), and others—pose major global health threats, yet most lack approved antiviral therapeutics. In the recent study, high-resolution cryo-electron microscopy (cryo-EM) revealed previously unrecognized allosteric pockets in the large (L) polymerase proteins of MeV and NiV, spatially distinct from the catalytic nucleotide-binding site. We further demonstrated that the non-nucleoside inhibitor ERDRP-0519 engages these pockets to allosterically ‘lock’ the polymerase in a mechanically inactive state. These findings reveal an allosteric mechanism of inhibition rooted in the conformational mechanics of the enzyme and highlight opportunities for integrating artificial intelligence (AI)-aided drug discovery (AIDD) into rational drug design.