Identification of a pyridopyrimidinone inhibitor of orthopoxviruses from a diversity-oriented synthesis library.
Orthopoxviruses include the prototypical vaccinia virus, the emerging infectious agent monkeypox virus, and the potential biothreat variola virus (the causative agent of smallpox). There is currently no FDA-approved drug for humans infected with orthopoxviruses. We screened a diversity-oriented synthesis library for new scaffolds with activity against vaccinia virus. This screen identified a nonnucleoside analog that blocked postreplicative intermediate and late gene expression. Viral genome replication was unaffected, and inhibition could be elicited late in infection and persisted upon drug removal. Sequencing of drug-resistant viruses revealed mutations predicted to be on the periphery of the highly conserved viral RNA polymerase large subunit. Consistent with this, the compound had broad-spectrum activity against orthopoxviruses in vitro. These findings indicate that novel chemical synthesis approaches are a potential source for new infectious disease therapeutics and identify a potentially promising candidate for development to treat orthopoxvirus-infected individuals.
Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, USA.
Ken
K
Dower
Claire Marie
CM
Filone
Erin N
EN
Hodges
Zach B
ZB
Bjornson
Kathleen H
KH
Rubins
Lauren E
LE
Brown
Scott
S
Schaus
Lisa E
LE
Hensley
John H
JH
Connor
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D006801:Humans; D015394:Molecular Structure; D018155:Orthopoxvirus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D011213:Poxviridae Infections / Q000821:virology; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000494:pharmacology*; D014779:Virus Replication
D000998:Antiviral Agents; D011744:Pyrimidinones; D054852:Small Molecule Libraries