Abstract Ebola viruses (EBOV) along with Marburg viruses (MARV) belong to the Filoviridae family which infects humans and nonhuman primates and causes outbreaks with a high mortality up to 90%. We do not have approved drugs for treating this deadly viral disease and therefore it is urgent to develop therapeutics to cope with the dangerous outbreaks. In this project, we propose to develop peptide based inhibitors targeting the receptor binding site (RBS) to block viral infection. We will conduct structure based design using the available co-crystal structures of the NPC1 receptor or monoclonal antibodies bound to the viral glycoprotein. The initial evaluation will utilize pseudo- typed viruses to test viral entry in a cell based assay. The best peptide candidates from these assays will subsequently be tested in a BSL-4 containment facility using replication competent viruses for entry inhibition tests. In vivo evaluations of qualified candidates will be conducted in a virus challenge mouse model to measure protection efficacy. After all these evaluations, promising candidates could be advanced to nonhuman primates or human clinical trials.