Identification of an antioxidant small-molecule with broad-spectrum antiviral activity.
The highly lethal filoviruses, Ebola and Marburg cause severe hemorrhagic fever in humans and non-human primates. To date there are no licensed vaccines or therapeutics to counter these infections. Identifying novel pathways and host targets that play an essential role during infection will provide potential targets to develop therapeutics. Small molecule chemical screening for Ebola virus inhibitors resulted in identification of a compound NSC 62914. The compound was found to exhibit anti-filovirus activity in cell-based assays and in vivo protected mice following challenge with Ebola or Marburg viruses. Additionally, the compound was found to inhibit Rift Valley fever virus, Lassa virus and Venezuelan equine encephalitis virus in cell-based assays. Investigation of the mechanism of action of the compound revealed that it had antioxidant properties. Specifically, compound NSC 62914 was found to act as a scavenger of reactive oxygen species, and to up-regulate oxidative stress-induced genes. However, four known antioxidant compounds failed to inhibit filovirus infection, thus suggesting that the mechanistic basis of the antiviral function of the antioxidant NSC 62914 may involve modulation of multiple signaling pathways/targets.
United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, Frederick, MD 21702-5011, USA.
Rekha G
RG
Panchal
St Patrick
SP
Reid
Julie P
JP
Tran
Alison A
AA
Bergeron
Jay
J
Wells
Krishna P
KP
Kota
Javad
J
Aman
Sina
S
Bavari
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001559:Benzhydryl Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D029043:Ebolavirus / Q000187:drug effects*; D016166:Free Radical Scavengers / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006367:HeLa Cells; D019142:Hemorrhagic Fever, Ebola / Q000188:drug therapy; D057166:High-Throughput Screening Assays; D006801:Humans; D008379:Marburg Virus Disease / Q000188:drug therapy; D029024:Marburgvirus / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
C571515:2-tert-butyl-6-((3-((3-tert-butyl-2-hydroxy-5-methylphenyl)methyl)-2-hydroxy-5-methylphenyl)methyl)-4-methylphenol; D000998:Antiviral Agents; D001559:Benzhydryl Compounds; D016166:Free Radical Scavengers; D010636:Phenols; D054852:Small Molecule Libraries