PROJECT SUMMARY/ABSTRACT - Overall SARS-CoV-2 continues to cause severe morbidity and mortality in the ongoing pandemic. Future RNA virus epidemics and pandemics are inevitable. New clinical-trial-ready antivirals are urgently needed RNA viruses of pandemic potential. COVID-19 has further underscored the need for early, global access to clinic-ready compounds. Beyond coronaviruses; flaviviruses and picornaviruses also cause frequent and ongoing epidemics worldwide and have no effective therapeutics. Maintaining a portfolio of novel, clinic-ready therapeutics are critical for our future pandemic preparedness. The AI-driven Structure-enabled Antiviral Platform (ASAP) AViDD Center will develop novel chemical assets that have antiviral activity against three target viral families. ASAP will leverage state-of-the-art structure-enabled technologies capable of leveraging recent advances in AI/ML and computational chemistry in identifying, enabling, and prosecuting discovery campaigns against novel viral targets. ASAP is built on principles of open science and rapid dissemination (enabled by a dedicated Data Infrastructure Core). ASAP builds on the successful COVID Moonshot, an open science collaboration that recently secured $11 million from the Wellcome Trust via the WHO Access to COVID Tools Accelerator (ACT-A) to fund preclinical development of a novel oral noncovalent SARS-CoV-2 antiviral acting against the main protease (MPro). Beginning with a high-throughput X-ray fragment screen, the discovery team spent just 18 months and $1M to reach the preclinical phase. ASAP will mirror this rapid, cost-efficient approach: automated structural biology at Diamond Light Source (Frank von Delft); AI/ML synthesis models from PostEra (Alpha Lee); nanoscale chemistry and covalent fragment libraries from Nir London; massively distributed free energy calculations on Folding@home (John Chodera); an industrial medicinal chemistry team led by MedChemica (Ed Griffen); and antiviral assays and virology expertise at Mount Sinai (Kris White; Adolfo García-Sastre). ASAP augments this seasoned antiviral discovery team with new approaches to resistance-robust targeting (Karla Kirkegaard and Matt Bogyo, Stanford) and deep mutational scanning (Jesse Bloom, Fred Hutch). ASAP is supported by the Drugs for Neglected Diseases Initiative (DNDi) (PI Ben Perry), and Letters of Support from Takeda, Pfizer, Novartis, and Grupo Insud. ASAP Impact: ASAP will become the nexus of a robust global antiviral discovery community. Our open science approach focuses on ensuring global, equitable access to therapeutics to combat future pandemics. We aim to produce a robust antiviral pipeline consisting of 3 new Phase I ready candidates, 6 lead optimization campaigns, 9 fragment-to-lead campaigns, and 10 structure-enabled resistance-robust viral targets. Our associated data packages will accelerate follow-on development and investment.