Revealing the molecular mechanisms of SARS-CoV-2 interaction with membranes to design inhibitors of viral entry and replication
Abstract: Infection by envelope viruses is mediated by fusion proteins on the virus surface and requires exposure of a fusion peptide (FP), which inserts into the target membrane. SARS-CoV-1 FP contains critical conserved acidic residues, binds calcium ions, and perturbs membranes in a calcium-dependent fashion. We hypothesize that the SARS-CoV-2 FP also binds calcium and that calcium is a critical determinant of FP membrane binding and perturbation and of SARS-CoV-2 cell entry. We will test this hypothesis as a basis for approaches to interfere with SARSCoV-2 fusion, including inhibitor design. We will use NMR spectroscopy and computer simulations to analyze the process of FP release and calcium binding, determine the structure of the calcium-bound FP, analyze the basis for and extent of membrane perturbation by the FP, and identify specific FP conformations as leads for blocker designs.
Activity : 2021-2022