Seminar: Putting the Brakes on Viral Assembly: Developing Broadly Active Antivirals for Emerging Paramyxoviruses

Abstract: Paramyxoviruses, such as Measles and Nipah virus, are among the most infectious and deadly viruses, with the potential to trigger a devastating pandemic. These viruses spread by assembling and budding from the plasma membrane of infected cells, a process coordinated by the viral matrix protein. This protein binds to the membrane and self-assembles into a lattice that connects the viral proteins to form virion particles. The matrix protein is structurally conserved across paramyxoviruses, making it a promising target for antiviral development. However, our understanding of the molecular interactions driving viral assembly, including how the matrix protein interacts with host membranes, remains incomplete. We demonstrate that matrix proteins from both viruses specifically interact with PI(4,5)P2 in the host plasma membrane, and that lattice formation occurs only in the presence of PI(4,5)P2. To gain insights into these interactions, we determined high-resolution structures of measles and Nipah matrix proteins, as well as the Nipah matrix protein in complex with a soluble form of PI(4,5)P2. This revealed a PI(4,5)P2-binding pocket, and that PI(4,5)P2 binding drives conformational rearrangements, facilitating lattice polymerization, membrane curvature, and virion assembly. Furthermore, we provide proof-of-principle that compounds reducing PI(4,5)P2 levels effectively inhibit both infections. These studies establish a framework for paramyxovirus assembly and reveal how future therapies might stop these viruses.