QCRG PANDEMIC RESPONSE PROGRAM OVERALL SUMMARY The QCRG (Quantitative Biosciences Institute Coronavirus Research Group) Pandemic Response Program is an interdisciplinary program that aims to identify new direct-acting antivirals for SARS-CoV-2 and 19 other viruses. The proposal brings together a team of 45 investigators from 14 different institutions with a history of collaboration; 31 of these have co-published together on 25 papers on SARS-CoV-2,1–25 efforts that have laid a strong foundation for the QCRG Pandemic Response Program. Initially, we will focus on eight target classes from eight viral families (Coronaviridae, Picornaviridae, Togaviridae, Flaviviridae, Hantaviridae, Arenaviridae, Nairoviridae and Paramyxoviridae), including seven coronaviruses, with a focus on SARS-CoV-2, where the viral RNA and 12 proteins will be targeted. In addition to the SARS-CoV-2 RNA (Project 1), we will target the Nsp3 PLP and Nsp5 Mpro proteases (Project 2); the Nsp3 macrodomain (Project 5); the RdRp polymerase, Nsp7, Nsp8 and Nsp12 (Project 2) the structural proteins E (Project 3), N (Project 6) and M (Projects 3 and 6); the methyltransferases Nsp10/16 and Nsp14 (Project 4); and the accessory protein involved in regulating the immune response, Orf9b (Project 6). Although we will focus on SARS-CoV-2, related proteins from 19 other viruses will also be targeted. Using the QCRG Drug Discovery Platform, we will perform screens on these targets, involving fragment campaigns, virtual library docking, and high-throughput screens, to discover inhibitors, which will be optimized using cycles of design, structure determination, and testing. In vitro and in vivo pharmacokinetics as well as activity in cellular and mouse models of infection will be carried out, followed by studies involving oral bioavailability, clearance, permeability, solubility, metabolic liabilities, toxicity and efficacy. The final goal of each Project is an Optimized Lead ready for clinical development at Roche (see Letter of Support from Dr. John Young, Head of Infectious Diseases) and other industry partners. Throughout, we will exploit an integrated suite of experimental and computational technologies provided by eight Cores. The Biochemistry Core will provide purified material for the Screening Core, while the structures of targets and compounds will be determined through the Cryo-EM, Cryo-ET and crystallography capabilities of the Structural Biology Core. State-of-the-art mass spectrometry in the Proteomics Core will provide mechanistic insight into the effects of compounds on their targets. The Medicinal Chemistry Core will optimize potent on- target compounds and work closely with the In Vitro Virology Core and In Vivo Virology Core to measure and optimize antiviral activity. The Integrative Modeling Core will provide computational support to structure determination and inhibitor discovery throughout the QCRG Drug Discovery Platform. The Administrative Core will provide leadership, help t...