Cryo-EM structures of Nipah virus polymerases and high-throughput RdRp assay development enable anti-NiV drug discovery
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 DiDonato,
Glen Spraggon,
Matthew C. Clifton,
Nadine Jarrousse,
Judith Straimer () and
Bo Liang ()
Additional contact information
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
Nature Communications, 2025, vol. 16, issue 1, 1-14
Abstract:
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.
Date: 2025
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61764-4
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DOI: 10.1038/s41467-025-61764-4
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