In the project “Targeting the replication machinery of Nipah virus” the aim is to solve the henipavirus replicase structure and identify inhibitors of replicase activity for the purpose of identifying new antivirals for pandemic preparedness. A three pronged approach will be followed to (1) solve the structure of Nipah and Cedar virus replicase complexes using cryo-EM in conjunction with fragment based screening and small molecule binders from the X-CHEM library to understand ligand-target interaction and (2) identify/validate hits (from the fragment screen and additional small molecule libraries) using minigenome Cedar virus screening assays and (3) identify host factors that bind Nipah virus polymerase using enzymatic assays coupled to proteomics. Additionally, nanobodies will be used to identify functionally important binding surfaces and active sites that inhibit different stages of replication. Novel binding factors of interest will be further analyzed using knockdown systems such as RNAi, Crispr or Degrons.The 3-year project was initiated in November 2022 and is hosted by University of Oxford, United Kingdom and the principal investigator is Professor Jonathan Grimes.
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