Drug discovery targeting SARS-CoV-2 membrane fusion.

Abstract

SARS-CoV-2 infect hosts by membrane fusion, a process where the virus membrane and host membrane merge together to allow the viral genetic material to enter the host cell. The viral membrane fusion is catalyzed by the viral spike protein (S). S, after receptor binding and proteolytic activation, dissociates into S1 and S2 subunits, the latter of which then goes through large conformational changes to bring the two membranes together. The heptad repeat 1 (HR1) and 2 (HR2) domains of S, that are far from each other in the primary sequence of S and spatially far apart in the prefusion structure of S, zipper into a 6-helix bundle in the postfusion S, which presumably provides the energy for overcoming the kinetic barrier of fusing membranes. We developed a method to efficiently determine high-resolution bundle structures by molecular scaffolding and cryogenic electron microscopy. We have utilized this method to study the structural conservation of the postfusion bundle, and to guide structure-based design of potent inhibitors. We have discovered an HR2-based peptide, named longHR2_42, that potently inhibits the infection by the wildtype SARS-CoV-2 and several variants with IC50 in the range of 1-4 nM.