A small-molecule probe for hepatitis C virus replication that blocks protein folding.
The hepatitis C virus (HCV) is a growing global health problem. Small molecules that interfere with host-viral interactions can serve as powerful tools for elucidating the molecular mechanisms of pathogenesis and defining new strategies for therapeutic development. Using a cell-based screen involving subgenomic HCV replicons, we identified the ability of 18 different abscisic acid (ABA) analogs, originally developed as plant growth regulators, to inhibit HCV replication. Three of these were further studied. One compound, here named origamicin, showed antiviral activity through the inhibition of host proteins involved in protein folding. Origamicin could therefore be an important tool for studying the maturation of both host and viral proteins. Herein we demonstrate an application for molecular scaffolds based on ABA for mammalian cell targets involved in protein folding.
Rakic
Bojana
B
The Steacie Institute for Molecular Sciences, National Research Council Canada, 100 Sussex Drive, Ottawa, Ontario K1A 0R6, Canada.
Clarke
Jennifer
J
Tremblay
Tammy-Lynn
TL
Taylor
Janet
J
Schreiber
Karl
K
Nelson
Ken M
KM
Abrams
Suzanne R
SR
Pezacki
John Paul
JP
D000040:Abscisic Acid / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000480:Alkynes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003512:Cyclohexanones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015967:Gene Expression Regulation, Viral / Q000187:drug effects / Q000235:genetics; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D008970:Molecular Weight; D017510:Protein Folding; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000187:drug effects*
D000480:Alkynes; D000998:Antiviral Agents; D003512:Cyclohexanones; C515679:origamicin; D000040:Abscisic Acid