1) Optimizing eCD4-Ig for eradication and a functional cure

SAR-CoV-2 (2019-nCoV) is a human pathogenic coronavirus that is very similar to the SARS coronavirus (SARS-CoV or SARS-CoV-1). As of this writing, more than 40,000 people are reported to be infected with this virus, causing more than 1,000 deaths. It is hoped that the number of new cases will decline precipitously in the coming weeks and months, and that newly available therapies can prevent more deaths. However, it is already clear that SARS-CoV-2 will remain a concern, real or potential, over the several next years. The team assembled here has extensive experience the study of SARS-CoV. We identified its receptor - also the receptor for SARS-CoV-2 - as ACE2 (Li et al., Nature 2003), delineated the receptor-binding domain (RBD) on the SARS-CoV spike (S) protein (Wong et al., J Biol Chem 2004), created the first efficient retroviral pseudotype system to study SARS-CoV S protein-mediated entry (Moore et al., J Virol 2004), identified and characterized a broad neutralizing antibody recognizing the RBD in collaboration with Wayne Marasco (Sui et al, PNAS, 2004), described the structure of the RBD bound to ACE2 with Stephen Harrison (Li et al., Science, 2005), described critical S-protein determinants of zoonosis and disease severity (Li et al., EMBO J, 2005), showed in separate collaborations with David Ho and Shibo Jiang that the S protein or the RBD alone can raise potent neutralizing antisera (Chen et al., J Virol 2005; He et al., J Immunol, 2006), and observed that cathepsin L was necessary for S protein-mediated infection (Huang et al., J Biol Chem, 2006). The current proposal seeks to apply this experience and the tools and approaches we developed for SARSCoV to: (1) develop, characterize, and optimize protein inhibitors of SARS-CoV-2 entry including immunoadhesin forms of ACE2, the SARS-CoV-2 RBD region, anti-ACE2 antibodies, and anti-S protein antibodies, (2) determine whether S-protein-trimers or the RBD, or a combination thereof, most efficiently raise SARS-CoV-2 neutralizing antibodies.