title: Identification of thieno[3,2-b]pyrrole derivatives as novel small molecule inhibitors of neurotropic alphaviruses.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Center for Chemical Genomics, Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan 48109-5688, USA.
authors.forename: Weiping
authors.initials: W
authors.lastname: Peng
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Peltier
authors.forename: Martha J
authors.initials: MJ
authors.lastname: Larsen
authors.forename: Paul D
authors.initials: PD
authors.lastname: Kirchhoff
authors.forename: Scott D
authors.initials: SD
authors.lastname: Larsen
authors.forename: Richard R
authors.initials: RR
authors.lastname: Neubig
authors.forename: David J
authors.initials: DJ
authors.lastname: Miller
mesh_terms: 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
chemical_list: D000998:Antiviral Agents; D011758:Pyrroles; D054334:Viral Regulatory and Accessory Proteins