ABSTRACTThe pandemic COronaVIrus disease 2019 (COVID-19) is an infectious disease which is caused by a novel andhighly pathogenic virus strain SARS-CoV-2 (Severe acute respiratory virus syndrome coronavirus 2). Theinfection may cause severe lower respiratory tract infection with acute respiratory distress and extrapulmonaryorgan disfunctions in infected individuals. Treatment strategy that both limits SARS-CoV-2 replication and reduceinflammation associated with COVID-19 would provide the greatest therapeutic benefit.Polyamines are naturally occurring organic cations that are essential for growth and development of bothprokaryotic and eukaryotic cells. Many viruses require host polyamines for replication in the infected cells andtargeting polyamine metabolism during viral infection showed promising results in in vitro and in vivo animalstudies. The goal of this proposal is to test the applicability of two currently FDA approved drugs eflornithine(other name -difluoromethylornithine or DFMO) and sulindac and their combination for prevention or treatmentof COVID-19 disease. Eftornithine is an irreversible inhibitor of a key polyamine biosynthetic enzyme ornithinedecarboxylase (ODC). Sulindac is a common non-steroidal anti-inflammatory drug (NSAIDs) which also inducespolyamine catabolism. Eflornithine and sulindac work in a complementary manner to reduce intracellularpolyamine levels. The safety doses of eflornithine/sulindac combination have been established for prevention ofrecurrence of high-risk adenomas (ClinicalTrials.gov Identifier NCT00118365).In this proposal we will test the hypothesis that eflornithine and sulindac combination will reduce both theintracellular polyamine availability for coronavirus replication and inflammation associated with COVID-19. Wewill test this hypothesis using cell culture models (Specific Aim 1) and mouse models of COVID-19 disease(Specific Aim 2). Planning activities in preparation for clinical trials for eflornithine/sulindac combination forantiviral indication in collaboration with Cancer Prevention Pharmaceuticals (CPP) (www.canprevent.com) arealso included.The translational goal of this project is to develop the effective approach for prevention COVID-19 infectionas well as decreasing severity of the viral infection in the COVID-19 patients. It is essential to developnew approaches to prevention and treatment of virus outbreaks.