title: Identification of a broad-spectrum inhibitor of viral RNA synthesis: validation of a prototype virus-based approach.
abstract: There are no approved therapeutics for the most deadly nonsegmented negative-strand (NNS) RNA viruses, including Ebola (EBOV). To identify chemical scaffolds for the development of broad-spectrum antivirals, we undertook a prototype-based lead identification screen. Using the prototype NNS virus, vesicular stomatitis virus (VSV), multiple inhibitory compounds were identified. Three compounds were investigated for broad-spectrum activity and inhibited EBOV infection. The most potent, CMLDBU3402, was selected for further study. CMLDBU3402 did not show significant activity against segmented negative-strand RNA viruses, suggesting proscribed broad-spectrum activity. Mechanistic analysis indicated that CMLDBU3402 blocked VSV viral RNA synthesis and inhibited EBOV RNA transcription, demonstrating a consistent mechanism of action against genetically distinct viruses. The identification of this chemical backbone as a broad-spectrum inhibitor of viral RNA synthesis offers significant potential for the development of new therapies for highly pathogenic viruses.
authors.affiliation: Department of Microbiology, School of Medicine, Boston University, Boston, MA 02118, USA.
authors.forename: Claire Marie
authors.initials: CM
authors.lastname: Filone
authors.forename: Erin N
authors.initials: EN
authors.lastname: Hodges
authors.forename: Brian
authors.initials: B
authors.lastname: Honeyman
authors.forename: G Guy
authors.initials: GG
authors.lastname: Bushkin
authors.forename: Karla
authors.initials: K
authors.lastname: Boyd
authors.forename: Andrew
authors.initials: A
authors.lastname: Platt
authors.forename: Feng
authors.initials: F
authors.lastname: Ni
authors.forename: Kyle
authors.initials: K
authors.lastname: Strom
authors.forename: Lisa
authors.initials: L
authors.lastname: Hensley
authors.forename: John K
authors.initials: JK
authors.lastname: Snyder
authors.forename: John H
authors.initials: JH
authors.lastname: Connor
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D029043:Ebolavirus / Q000187:drug effects* / Q000235:genetics* / Q000254:growth & development / Q000502:physiology; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D006801:Humans; D012367:RNA, Viral / Q000096:biosynthesis*; D014158:Transcription, Genetic / Q000187:drug effects; D018116:Vesiculovirus / Q000187:drug effects* / Q000235:genetics* / Q000254:growth & development / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D012367:RNA, Viral