Structural basis of measles virus polymerase inhibition by nonnucleoside inhibitor ERDRP-0519

TL;DR

Scientists discovered how a drug called ERDRP-0519 blocks the measles virus by binding to a specific part of its polymerase enzyme.

Contribution

The study reveals the structural mechanism of ERDRP-0519 inhibition and identifies a unique binding pocket in the MeV polymerase.

Findings

ERDRP-0519 binds to a unique pocket in the RdRp palm subdomain of the MeV polymerase.

The compound overlaps with the catalytic GDN motif, explaining resistance mutations like W671.

The findings provide a structural basis for developing improved antiviral drugs against Morbilliviruses.

Abstract

ERDRP-0519 is a potent nonnucleoside inhibitor active against measles virus (MeV) and other Morbilliviruses. Here we report cryo-EM structures of the compound bound to MeV polymerase complexes at 2.73 Å and 2.48 Å resolution, revealing a unique binding pocket in the RdRp palm subdomain that overlaps the catalytic GDN motif. These findings clarify the basis of resistance mutations, including W671, and provide a foundation for designing next-generation Paramyxovirus antivirals.

ERDRP-0519 is a potent nonnucleoside inhibitor of Morbilliviruses. In this work, authors solve cryo-EM structures that reveal ERDRP-0519 bound to measles RNA polymerase in a unique RdRp palm pocket, clarifying resistance mutations and guiding next-generation antivirals.

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