New heterocyclic inhibitors of filoviruses

DESCRIPTION provided by applicant Ebola and Marburg 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 the biosafety level agents Currently there is no effective vaccine or therapeutic treatment against filoviral infection and pathogenesis in humans Although several promising vaccine candidates have been shown to be effective in eliciting host immune responses and to protect primates against viral infection the minimal time required for vaccination at least one month and the sporadic nature of outbreaks reinforce the urgent need to develop potent small molecule inhibitors against filoviral infections Thus it is imperative t identify and develop potent inhibitors against filoviral infection These inhibitors are considered to be of paramount importance for use during filoviral outbreaks or bioterrorist attacks This application defines a plan to develop potent small molecule inhibitors which block entry of Ebola and Marburg viruses Entry of Ebola and Marburg viruses into the hosts is mediated by a single viral glycoprotein GP which is considered one of the major therapeutic targets GP consists of two subunits GP and GP GP is responsible for receptor binding and host tropism while GP mediates viral cell membrane fusion and viral entry We have used an HTS protocol targeting GP mediated viral entry to screen a small molecule library and we have identified compounds that inhibit entry of infectious Ebola Marburg viruses IC values M These hit compounds exhibit selectivity for Ebola Marburg entry The overall objective of this Phase I application is to develop these inhibitors as potential anti filoviral therapeutics Tis application will focus on the following three specific aims Synthesize structurally diverse analogs of the anti Ebola hit series 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 Ebola Marburg inhibitors Select EBOV MARV 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 and Marburg viral infection The proposed research will help to develop potential antiviral therapeutics