Competitive Inhibition of the Nipah Virus Matrix Protein by Conivaptan: From Binding Pocket Dynamics to Protein-Membrane Interactions

The recurrent outbreaks of Nipah virus since its first emergence have intensified efforts to identify effective antiviral therapeutics. The matrix protein is a key structural protein that maintains virion architecture and plays a crucial role in anchoring the virus to the host plasma membrane. Binding of phosphatidylinositol-4,5-bisphosphate (PIP2) to the matrix protein promotes conformational changes that facilitate membrane association and initiate viral assembly. Therefore, an effective small-molecule inhibitor should not only compete with PIP2 for binding to the Nipah virus matrix protein (NiVM) but also disrupt its interaction with the host membrane. Using virtual screening of FDA-approved drugs combined with ensemble docking, we identified Conivaptan as a potential inhibitor of the Nipah virus matrix protein. The multivalent interactions of Conivaptan establish stable binding within the PIP2-binding pocket while simultaneously rewiring protein-membrane interactions. In the presence of PIP2, NiVM anchors to the membrane through multiple charged residues, resulting in pronounced local bilayer deformation, an early signature of membrane remodeling. In contrast, Conivaptan binding weakens membrane anchoring and preserves a more ordered and compact bilayer, thereby suppressing membrane deformation. Together, these findings identify Conivaptan as a promising repurposable inhibitor of the Nipah virus matrix protein and provide a mechanistic framework for targeting virus-membrane interactions during viral assembly.