Seminar: Molecular Architecture of the Nipah Virus Polymerase Complex and Antiviral Development Strategies

ABSTRACT

Nipah virus, recognized by the WHO as a priority pathogen, poses a recurrent threat by causing severe respiratory and neurological disease with case fatality rates reaching up to 70%. Despite its lethality, no licensed therapeutics are currently available. Central to Nipah virus replication is the viral polymerase complex, composed of the large polymerase (L) protein and its cofactor, the phosphoprotein (P), which together replicate and transcribe the viral RNA genome. Using cryo-electron microscopy, we determined the structure of the Nipah virus L-P polymerase complex, revealing the organization of the RNA-dependent RNA polymerase (RdRp) and polyribonucleotidyl transferase (PRNTase) domains within L, and showing how the tetrameric P protein engages the RdRp domain to stabilize and regulate polymerase activity. Complementary crystallographic analysis of the L-protein’s Connecting Domain (CD) identified binding of multiple Mg ions, suggesting a catalytic role in mRNA capping. Extending these structural insights, we further defined how nanobodies can target and inhibit the polymerase by locking it into inactive conformations. Together, these findings illuminate key molecular mechanisms of the Nipah virus replication machinery and provide a structural framework for the rational design of antiviral strategies, including nanobody-based therapeutics.

BIOGRAPHY

Dr. Esra Balıkçı Akıl earned her BSc in Molecular Biology and Genetics from IZTECH in 2015 and her PhD in Biochemistry from A*STAR / National University of Singapore (NUS) in 2021. Her doctoral research focused on understanding the structural and biochemical mechanisms of the Hippo signalling pathway and developing small-molecule inhibitors, uncovering a potential therapeutic strategy for regenerative medicine. She then joined the University of Oxford’s Centre for Medicines Discovery, where she contributed to hit-to-lead drug development and the design of small-molecule inhibitors and degraders for oncogenic targets. Currently, she is part of the Structural Virology group at the University of Oxford, studying RNA viruses classified as WHO priority pathogens. Her research integrates biochemical and biophysical approaches with cryo-electron microscopy, X-ray crystallography, and cryo-electron tomography to advance antiviral drug discovery