In response to the Notice of Special Interest regarding the Availability of Emergency Competitive Revisions for research on SARS-CoV-2 and COVID-19 (NOT-AI-20-034), the proposal herein is focused on the development of SARS-CoV-2 therapeutic candidates with broad-spectrum activity against multiple coronavirus strains. It is submitted as an Emergency Competitive Revision (PA-20-135) to an existing NIAID SBIR Phase II award titled “A single antiviral to treat multiple opportunistic infections” (R44AI114079). The existing Phase II award is based on the discovery that human sirtuin-2 protein (SIRT2) modulates the replication and spread of many different viruses. The applicant, Evrys Bio, LLC, has developed a lead series of >550 SIRT2 inhibitors that exhibit broad- spectrum antiviral activity. Excellent progress for the existing award has been made in the identification of a Development Candidate ready for IND-enablement (DC). The candidates for DC selection show broad-spectrum activity against human cytomegalovirus (HCMV) and other opportunistic agents causing disease in immunosuppressed transplant patients. Indeed, Evrys SIRT2 inhibitors block the growth of many different viruses in addition to HCMV, including DNA viruses (Epstein-Barr virus, BK virus, Hepatitis B virus) and RNA viruses (influenza A and B, respiratory syncytial virus, Zika virus, Junin virus, Marburg virus and coronaviruses). Of special relevance to this application, an Evrys SIRT2 inhibitor was shown to inhibit the production of progeny by the human alpha-coronavirus HCoV-229E (EC50 = 1.6 µM) and beta-coronavirus HCoV-OC43 (EC50 = 0.54 µM). OC43 was studied in greater detail, and production of its N and M RNA as well as N protein were dramatically inhibited in human MRC-5 cells. This proposal leverages the funding and progress of the existing SBIR Phase II award to identify and advance a Development Candidate with broad-spectrum antiviral activity. Proposed competitive revision Specific Aims focus on development of SARS-CoV-2 aspects of the broad- spectrum therapeutic: SARS-CoV-2 activity will be tested to select the DC from among nine SIRT2 inhibitors (active against beta-coronavirus OC43) already satisfying Target Compound Profile criteria for development including broad-spectrum antiviral effectiveness and suitability for pharmaceutical development. To speed a therapeutic solution to patients in need, the selected broad-spectrum DC (including SARS-CoV-2 antiviral activity) will be advanced through IND enabling studies. In parallel, a back-up DC will be obtained. Evrys has extensively characterized the lead series with respect to quantitative structure activity relationships (QSAR) predicting HCMV antiviral activity and allowing for optimization of pharmaceutical properties. The algorithms will be retrained for coronavirus to select a back-up optimized for coronavirus potency and pharmaceutical properties (e.g., good lung distribution) for treatment of COVID-19. Extension of the p...