GPCR antagonists as anti-Ebola virus entry inhibitors

DESCRIPTION provided by applicant Ebola EBOV and Marburg MARV viruses belong to the family Filoviridae and can cause fatal hemorrhagic fevers characterized by widespread tissue destruction with an incubation period of days Because of the safety concerns these viruses are designated as biosafety level agents Currently there is no effective vaccine or therapeutic treatment against filoviral infection and pathogenesis in humans The current ongoing Ebola epidemic in West Africa has led to more than deaths and underscores the global challenge of treating and controlling this deadly virus This application defines a plan to identify and develop potent small molecule inhibitors which block entry of EBOV into host cells We have developed a cell based HTS protocol targeting Ebola entry to identify small molecule inhibitors that block entry of infectious EBOV The overall objective of this Phase I application is to identify and develop these inhibitors as potential anti Ebola therapeutics This application will focus on the following three specific aims Identify potent anti Ebola inhibitors from a small molecule library of GPCR antagonists prioritize and chemically modify the most potent inhibitors based on structure activity relationships SARs to improve potency and selectivity Validate the lead inhibitor candidates in the infectious assay and investigate the mechanism of action MOA of the EBOV inhibitors Select EBOV inhibitors with in vitro ADME properties suitable for i v and oral dosing PUBLIC HEALTH RELEVANCE This project is to discover and develop small molecule entry inhibitors for Ebola viral infection The proposed research will help to develop potential antivira therapeutics