Research Abstract

The central goal of our research is to understand how enveloped viruses enter cells. Recently, we have focused heavily on chemical biology-based approaches. Initially, we identified a small molecule that targets NPC1 and inhibits binding to EBOV GP. We found this compound inhibits infection by competing with cholesterol for binding to NPC1, which is a required co-factor for receptor function. Our studies show the inhibitor binding locks NPC1 in a specific conformation that is not recognized by the virus glycoprotein. During iterative optimization of this inhibitor, we discovered that a closely related analog is a highly specific inhibitor of the pathogenic arenavirus, Lassa fever virus (LASV). Our studies show that the LASV inhibitor competes with cholesterol for binding to the LASV receptor, LAMP1. Thus, we have identified a potential “Achilles heel” for two distinct pathogenic viruses that can targeted by specific compounds that share the N-benzyl piperazine scaffold. We are now developing bi-functional photo-reactive/clickable analogs based on this scaffold to probe for new targets in sterol dependent virus and cancer pathways.