2. Academic Validation
  3. Structures of the measles virus polymerase complex with non-nucleoside inhibitors and mechanism of inhibition

Structures of the measles virus polymerase complex with non-nucleoside inhibitors and mechanism of inhibition

  • Cell. 2025 Sep 4;188(18):4913-4923.e13. doi: 10.1016/j.cell.2025.06.017.
Yiru Wang 1,  Lixia Zhao 2,  Yi Zhang 2,  Xiuxia Gao 2,  Yannan Wang 2,  Wenping Shi 2,  Roger D Kornberg 3,  Heqiao Zhang 4
Affiliations

Affiliations

  • 1 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 2 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China.
  • 3 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: kornberg@stanford.edu.
  • 4 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China. Electronic address: zhanghq@shanghaitech.edu.cn.
PMID: 40628260 DOI: 10.1016/j.cell.2025.06.017
Abstract

The measles virus (MeV), a highly contagious non-segmented negative-sense RNA virus in the Paramyxoviridae family, causes millions of infections annually, with no approved antivirals available. The viral polymerase complex, comprising the large (L) protein and the tetrameric phosphoprotein (P), is a key Antiviral target. We determined the cryo-electron microscopy structures of the MeV polymerase complex alone and bound to two non-nucleoside inhibitors, ERDRP-0519 and AS-136A. Inhibitor binding induces a conformational change in the catalytic loop, allosterically locking the polymerase in an inactive "GDN-out" state. These findings led to the proposal that ERDRP-0519 would also be effective against Nipah virus (NiV), a highly pathogenic virus with no available antivirals. This proposal was confirmed by structure determination of the NiV polymerase complex and by inhibition of transcription.

Keywords

AS-136A; ERDRP-0519; L-P complex; Nipah virus; cryo-EM; measles virus; non-nucleoside inhibitor; polymerase complex.

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