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 mos...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.展开更多
基金supported by a grant from ShanghaiTech University to H.Z.,and a grant from the Shanxi Key Laboratory of Protein Structure Determination(202104010910006)to H.Z.
文摘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.
