Optimization of Ebola Virus Entry Inhibitors

Infection by several Ebola virus species is associated with severe viral hemorrhagic feverVHFin humansTo datesignificant Ebola virus outbreaks in central and western Africa have been associated with the EbolaZaireEBOVSudanSUDVand BundibugyoBDBVspecies with case fatality rates ranging fromDuring theEBOV outbreakpeople died from Ebola VHFGiven the lack of approved treatments and prophylacticsthe high mortality rate associated with infectionand the potential for geographical transplantation the development of broad spectrum Ebola virus antivirals for the treatment and prophylaxis of VHF remains an NIAID high priorityIn this proposal we detail plans to optimize an attractive hit to lead chemical series of Ebola virus cell entry inhibitors utilizing VSV pseudotype viruses expressing Ebola virus glycoproteins along with confirmatory BLSnative virus assays and initial vitro and in vivo ADMET studies to provide a lead compound compatible with oral administration for proof on concept studies in an in vivo animal efficacy model Several species of Ebolavirus are associated with severe hemorrhagic fevers exhibiting high fatality rates and are recognized as NIAID Category A high priority pathogensThe development of oral broad spectrum Ebolavirus antivirals could help to provide needed therapeutic treatments and prophylactics