Differential inhibition of Morbillivirus and Henipavirus polymerases by ERDRP-0519 and structure-guided inhibitor optimization.

Summary

Using structural and biochemical analyses, the authors show that ERDRP-0519 binds a conserved palm-domain pocket in paramyxovirus polymerases, cross-inhibiting Nipah virus with lower affinity due to required motif rearrangements. Structure-guided derivatives (GL22, G671) engage additional RdRp contacts, sterically block RNA/nucleotide binding more effectively, and enhance inhibition potency.

Key Findings

• ERDRP-0519 cross-inhibits Nipah virus polymerase but with reduced potency versus morbilliviruses.
• The inhibitor binds a conserved RdRp palm-domain pocket; NiV binding requires motif rearrangements, lowering affinity.
• ERDRP-0519 sterically blocks RNA and nucleotide binding, suppressing RNA synthesis.
• Structure-guided derivatives GL22 and G671 increase RdRp contacts and enhance biochemical inhibition.

Clinical Implications

While preclinical, the identification of a conserved polymerase pocket and improved derivatives supports development of broad-spectrum therapeutics against measles outbreaks and henipavirus threats, with potential to complement vaccines and outbreak response.

Limitations

• Preclinical study without in vivo efficacy or pharmacokinetic data.
• Resistance pathways and safety profiles of new derivatives remain to be defined.

Future Directions

Evaluate in vivo efficacy, resistance selection, and safety; optimize ADME for GL22/G671; assess breadth across paramyxoviruses and combinations with immunization/outbreak control.