Rapid Hit Generation and Lead Elaboration for SARS-CoV-2 Therapeutics

The novel SARS coronavirus (SARS-CoV-2) global pandemic has taken a strong foothold and itis estimated that it will infect hundreds of millions of people, with millions dying. These estimatesunderscore the severity of the COVID-19 disease, caused by SARS-CoV-2, yet there are currentlyno effective treatments that can be administered to infected individuals. Our approach centeredaround a proprietary structure-based drug discovery engine, which combines rapid screening ofa molecular fragment library in a fragment-based drug discovery approach with high-throughputX-ray crystallography. We will discover and develop novel small molecule inhibitors of the receptorbinding domain (RBD) of the SARS-CoV-2 viral spike protein S1 subunit (attachment inhibitors),inhibitors of the viral spike protein S2 subunit (fusion inhibitors), and the Nsp14-Nsp10 complex(replication mismatch repair inhibitors). Our approach resolves an important step in early drugdiscovery, i.e., the generation of reliable, high-quality, target-specific hits that can be advanced totherapeutics development. Our method provides experimental validation and unprecedentedability to visualize 3D protein-ligand interactions in a single step, delivering valuable actionableassets (identification and definition of binding sites and binding pose) for immediate chemistryand biology follow up in early drug discovery. Our goal is to target conserved amino acid residueswithin these proteins to discover and advance molecules that may inhibit the SARS-CoV-2proteins and also serve as pan-coronavirus inhibitors. Thus we will create broad-spectrumantiviral therapeutics against multiple coronavirus strains and against the homologous proteins inSARS and MERS, thereby effectively creating treatments for both current and future coronavirusoutbreaks. We will determine X-ray crystal structures of the SARS-CoV-2 RBD, S2 and Nsp14-Nsp10 proteins bound to molecular fragments and elaborate these fragment hits into inhibitorsthrough a combination of computational and medicinal chemistry, high-throughput structuralbiology, and biophysical assays.