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Cryo-EM structures of Nipah virus polymerases and high-throughput RdRp assay development enable anti-NiV drug discovery

Author

Listed:
  • Zhenhang Chen

    (Emory University School of Medicine)

  • Jeanne Quirit Dudley

    (Novartis)

  • Colin Deniston

    (Novartis)

  • Cosmo Z. Buffalo

    (Novartis)

  • Debjani Patra

    (Novartis)

  • Dongdong Cao

    (Emory University School of Medicine)

  • Julia Hunt

    (Emory University School of Medicine)

  • Ahmed Rohaim

    (Novartis)

  • Debapriya Sengupta

    (Novartis)

  • Lan Wen

    (Emory University School of Medicine)

  • Tiffany Tsang

    (Novartis)

  • Lili Xie

    (Novartis)

  • Michael DiDonato

    (Novartis)

  • Glen Spraggon

    (Novartis)

  • Matthew C. Clifton

    (Novartis)

  • Nadine Jarrousse

    (Novartis)

  • Judith Straimer

    (Novartis)

  • Bo Liang

    (Emory University School of Medicine)

Abstract

Transcription and replication of the Nipah virus (NiV) are driven by the large protein (L) together with its essential co-factor phosphoprotein (P). L encodes all the viral enzymatic functions, including RNA-dependent RNA polymerase (RdRp) activity, while the tetrameric P is multi-modular. Here, we investigate the molecular mechanism of the NiV polymerase and build tools for anti-NiV drug discovery. We analyze and compare multiple cryo-EM structures of both full-length and truncated NiV polymerases from the Malaysia and Bangladesh strains. We identify two conserved loops in the polyribonucleotidyltransferase (PRNTase) domain of L and the binding between RdRp-PRNTase and CD domains. To further assess the mechanism of NiV polymerase activity, we establish a highly sensitive radioactive-labeled RNA synthesis assay and identify a back-priming activity in the NiV polymerase as well as a fluorescence and luminescent-based non-radioactive polymerase assay to enable high-throughput screening for L protein inhibitors. The combination of structural analysis and the development of both high-sensitive and high-throughput biochemical assays will enable the identification of new direct-acting antiviral candidates for treating highly pathogenic henipaviruses.

Suggested Citation

  • Zhenhang Chen & Jeanne Quirit Dudley & Colin Deniston & Cosmo Z. Buffalo & Debjani Patra & Dongdong Cao & Julia Hunt & Ahmed Rohaim & Debapriya Sengupta & Lan Wen & Tiffany Tsang & Lili Xie & Michael , 2025. "Cryo-EM structures of Nipah virus polymerases and high-throughput RdRp assay development enable anti-NiV drug discovery," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61764-4
    DOI: 10.1038/s41467-025-61764-4
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