Infection by several Ebola virus species is associated with severe viral hemorrhagic fever (VHF) in humans. To date, significant Ebola virus outbreaks in central and western Africa have been associated with the Ebola- Zaire (EBOV), Sudan (SUDV) and Bundibugyo (BDBV) species with case-fatality rates ranging from 40-90%. During the 2014-2016 EBOV outbreak ~ 11,325 people died from Ebola VHF. Given the lack of approved treatments and prophylactics, the high mortality rate associated with infection, and the potential for geographical transplantation the development of broad spectrum Ebola virus antivirals for the treatment and prophylaxis of VHF remains an NIAID high priority. In 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 BLS4 native 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.
Public Health Relevance Statement: Several species of Ebolavirus are associated with severe hemorrhagic fevers exhibiting high fatality rates and are recognized as NIAID Category A high priority pathogens. The development of oral broad-spectrum Ebolavirus antivirals could help to provide needed therapeutic treatments and prophylactics.
NIH Spending Category: Biodefense; Emerging Infectious Diseases; Infectious Diseases; Orphan Drug; Rare Diseases
Project Terms: analog; animal efficacy; Animals; Antiviral Agents; Binding Proteins; Biological Assay; Blood Chemical Analysis; Body Weight; Cardiac; Case Fatality Rates; Categories; Cells; Central Africa; Characteristics; Chemicals; Clinical; Clinical Treatment; cytotoxicity; Democratic Republic of the Congo; Development; Disease Outbreaks; Dose; Drug Interactions; Drug Kinetics; Ebola Hemorrhagic Fever; Ebola virus; efficacy study; Engineering; Exhibits; Family; Family member; Fatality rate; Filovirus; Geography; Glycoproteins; Human; improved; In Vitro; in vivo; in vivo evaluation; Infection; inhibitor/antagonist; Lead; Liquid substance; Liver Microsomes; Marburgvirus; Maximum Tolerated Dose; Modeling; mortality; mouse model; Mus; Mutation; National Institute of Allergy and Infectious Disease; novel; Oral; Oral Administration; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Plasma; priority pathogen; Property; prophylactic; Prophylactic treatment; Safety; Series; Structure; Sudan; Sudan Ebola virus; Testing; Therapeutic; Transplantation; Vesicular stomatitis Indiana virus; Viral; Viral Hemorrhagic Fevers; viral resistance; Viremia; Virus; Western Africa; Zaire Ebola virus
