An antiviral weapon originally developed to target the measles virus has now been fine‑tuned by scientists to combat the deadly Nipah virus (NiV). A recent study published in Cell has uncovered the molecular basis for the cross-genus inhibition of paramyxovirus polymerases by the antiviral compound ERDRP-0519 and developed inhibitors with enhanced activity against NiV.

The research was carried out by the Guangzhou Institutes of Biomedicine and Health (GIBH) of the Chinese Academy of Sciences, in collaboration with researchers from Shandong University, Wuhan Institute of Virology, Guangzhou Laboratory and Guangzhou Medical University.

ERDRP-0519 is a non-nucleoside inhibitor originally developed against measles virus (MeV). In this study, through a combination of structural and biochemical analyses, cell-based assays, and antiviral studies using authentic virus, the researchers found that the compound can also cross-inhibit polymerases from the Henipavirus genus, including NiV, although its potency is reduced.

Using cryo-electron microscopy, the researchers determined the structures of polymerases from MeV, peste des petits ruminants virus (PPRV), and NiV in complex with ERDRP-0519. Structural analyses revealed that ERDRP-0519 binds to a conserved pocket within the palm domain of the viral RNA-dependent RNA polymerases (RdRp). Occupation of this pocket sterically blocks RNA template and nucleotide binding, thereby suppressing viral RNA synthesis.

The structural data further revealed that ERDRP-0519 binding to the NiV polymerase requires more extensive conformational rearrangements than binding to the polymerases of MeV and PPRV, both of which belong to the Morbillivirus genus. These larger conformational rearrangements required for ERDRP-0519 binding to the NiV polymerase likely lead to a higher energetic cost, thereby reducing binding affinity and contributing to the lower inhibitory activity observed against NiV.

Leveraging these mechanistic insights, the researchers performed structure-guided optimization of ERDRP-0519, yielding two derivatives: GL22 and G671. Structural and cellular assays revealed that the optimized compounds establish additional cross-domain interactions with the NiV polymerase, leading to enhanced inhibition of viral RNA synthesis.

Collectively, this work provides a molecular framework for understanding cross-genus inhibition of paramyxovirus polymerases and highlights how structural differences within a conserved drug-binding pocket can influence antiviral efficacy. The findings further establish a structure-guided strategy for developing next-generation polymerase inhibitors against NiV and other medically important paramyxoviruses.

The co-first authors are Dr. XUE Lu, GUI Jiacheng, GAO Shenghua, GAO Xiaoxiao, CHANG Tiancai, and PAN Hainei, who contributed equally to this work. The co-corresponding authors are Prof. XIONG Xiaoli and Prof. HE Jun from GIBH, Prof. ZHAN Peng from Shandong University, Prof. PEI Rongjuan from the Wuhan Institute of Virology, and Prof. CHEN Xinwen from Guangzhou Laboratory.

The study was supported by international collaborations with Prof. RONG Lijun at the University of Illinois Chicago and Prof. Richard K. Plemper at Georgia State University. Prof. Plemper originally developed the antiviral compound ERDRP-0519.

ERDRP-0519 binds Morbillivirus polymerases with higher affinity than the NiV polymerase. Guided by structural insights, the optimized derivative G671 incorporates an extended chemical moiety that establishes additional cross-domain interactions within the polymerase, resulting in improved binding to the NiV polymerase. (Image by GIBH)