Our project aims at rapidly testing medications that are FDA approved to treat other viral infections for their ability to inhibit the SARS-CoV-2 polymerase as therapeutics and PrEP for COVID-19. SARS-CoV-2 uses an RNA-dependent RNA polymerase (RdRp) catalyzed reaction to replicate its genome. RdRp in coronaviruses is a precise and well-defined drug target. Based on our analysis of hepatitis C virus, HIV and coronavirus replication, and the molecular structures and activities of viral inhibitors, we developed a rapid and efficient polymerase assay at the molecular level to precisely identify the SARS-CoV-2 RdRp inhibitory activities of FDA-approved nucleotide antivirals for other conditions. We demonstrated that the active triphosphate forms of 10 FDA-approved medications (Sofosbuvir, AZT, Tenofovir Alafenamide, Emtricitabine, Stavudine, Cidofovir, Ganciclovir, Abacavir, Entecavir and Didanosine) for treating other virus infections inhibit SARS-CoV-2 RdRp. We also demonstrated that the triphosphates of tenofovir and emtricitabine, the two components in DESCOVY used as pre-exposure prophylaxis (PrEP) to prevent HIV infection, act as terminators for the SARS-CoV-2 RdRp catalyzed reaction. Our preliminary experimental data provide a molecular basis to (1) evaluate the potential of the 10 FDA-approved medications identified above as therapeutics for COVID-19; and (2) evaluate the potential of these medications, in particular DESCOVY, for COVID-19 PrEP.