Identification of thieno[3,2-b]pyrrole derivatives as novel small molecule inhibitors of neurotropic alphaviruses.
Neurotropic alphaviruses such as western, eastern, and Venezuelan equine encephalitis viruses cause serious and potentially fatal central nervous system infections in humans and are high-priority potential bioterrorism agents. There are currently no widely available vaccines or licensed therapies for these virulent pathogens. To identify potential novel antiviral drugs, we developed a cell-based assay with a western equine encephalitis virus replicon that expresses a luciferase reporter gene and screened a small molecule diversity library of 51,028 compounds. We identified and validated a thieno[3,2-b]pyrrole compound with a half maximal inhibitory concentration of <10 micromol/L, a selectivity index>20, and potent activity against live virus in cultured neuronal cells. Furthermore, a structure-activity relationship analysis with 20 related compounds identified several with enhanced activity profiles, including 6 with submicromolar half maximal inhibitory concentrations. In conclusion, we have identified a novel class of promising inhibitors with potent activity against virulent neurotropic alphaviruses.
Peng
Weiping
W
Department of Internal Medicine, Center for Chemical Genomics, Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan 48109-5688, USA.
Peltier
Daniel C
DC
Larsen
Martha J
MJ
Kirchhoff
Paul D
PD
Larsen
Scott D
SD
Neubig
Richard R
RR
Miller
David J
DJ
D000524:Alphavirus / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001681:Biological Assay; D002460:Cell Line; D002522:Chlorocebus aethiops; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D054334:Viral Regulatory and Accessory Proteins / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D011758:Pyrroles; D054334:Viral Regulatory and Accessory Proteins