CV19: Identification of SARS-CoV-2 entry blockers with structure-guided screens of large chemical libraries

COVID-19. a debilitating disease. represents the single major world-wide health issue that needs to be addressed urgently. The severe acute respiratory syndrome coronavirus 2 virus (SARS-CoV-2). the causative agent of COVID-19. is a highly infectious virus for whichthere is no effective treatment. Entry of enveloped viruses such as SARS-CoV-2. into their host cells involves several steps that can be targeted individually for therapeutic intervention.including protein-protein interactions between viral proteins and host cell receptors. A protein called Glycoprotein-S. which is expressed on the surface of SARS-CoV-2. mediates the entry of the virus into human cells. A domain within Glycoprotein-S protein called the Receptor Binding Domain (RBD) directly binds to the Angiotensin Converting Enzyme 2 (ACE2) which is expressed on the surface of lung epithelial cells. The interaction between RBD and ACE2 is a critical event that is required for the entry of SAR-CoV-2 into cells.Therefore. the goal of the present proposal is to identify molecules that target the binding interface between the receptor binding domain (RBD) of the SARS-CoV-2 spike glycoprotein on the virion surface and the major receptor for SARS-CoV-2. angiotensin converting enzyme 2 (ACE2). The structure of the SARS-CoV-2 RBD in complex with ACE2 has been reported by three independent groups(2-4). These studies identified three specific sites of interaction of the SARS-CoV-2 RBD with the alpha-1 helix of ACE2. providing critical insight on the molecular basis for SARS-CoV-2 infection. We propose studies that combine virology. high-throughput screening. medicinal chemistry and in-silico drug design expertise to identify molecules that disrupt binding of SARS-CoV-2 to ACE2 and validate their potential to block SARS-CoV-2 entry to cultured epithelial cells.We expect to identify candidate drug leads that will be tested in animal models. likely as multidrug combination therapies.