CORE 3: MEDICINAL CHEMISTRY SUMMARY Despite the development of effective vaccines to address the COVID-19 pandemic, the significant challenges associated with their distribution and administration on a global scale, combined with the issue of vaccine hesitancy, has put a spotlight on the equally urgent need for safe and effective antiviral therapeutics. A readily distributed, orally bioavailable small molecule antiviral agent could play an outsized role in the continuing response to COVID-19 and in future pandemics by reducing the severity of disease for those at highest risk for serious outcomes and thereby curtailing the strain that serious illness puts on hospitals and healthcare infrastructure. The role of the Medicinal Chemistry Core in the larger QCRG Pandemic Response Program is to enable the Project teams to translate their expert knowledge of specific viral families and protein targets into small molecule drug leads that our industry partner Roche could rapidly develop into effective new antiviral therapies. Drug discovery is a highly collaborative enterprise requiring diverse scientific and technical expertise, and this is reflected in the Projects and Cores assembled as part of the QCRG Pandemic Response Program (see Fig. 1). Turning a validated screening ‘hit’ into a drug lead involves an iterative process of compound design and chemical synthesis that is characterized not only by optimization of ligand–target binding, but equally importantly by the optimization of in vivo ‘drug-like’ properties to ensure the molecule will reach its target in an animal and provide a sustained inhibitory effect that produces clinical efficacy. The Medicinal Chemistry Core will leverage the decades of drug discovery experience of its Core Lead Dr. Renslo and Co-Is Dr. Jin and Dr. Shoichet, the expertise of the Projects and Cores, and ADME and PK/Tox assays available at CROs, to convert validated hits into Optimized Leads, guided along this path by our Target Product Profile (TPP) for an antiviral small molecule therapeutics. These Optimized Leads will then be transferred to our industry partner Roche for further pre-clinical and clinical development.