title: Design and synthesis of an activity-based protein profiling probe derived from cinnamic hydroxamic acid.
abstract: In our continued effort to discover new anti-hepatitis C virus (HCV) agents, we validated the anti-replicon activity of compound 1, a potent and selective anti-HCV hydroxamic acid recently reported by us. Generally favorable physicochemical and in vitro absorption, distribution, metabolism, and excretion (ADME) properties exhibited by 1 made it an ideal parent compound from which activity-based protein profiling (ABPP) probe 3 was designed and synthesized. Evaluation of probe 3 revealed that it possessed necessary anti-HCV activity and selectivity. Therefore, we have successfully obtained compound 3 as a suitable ABPP probe to identify potential molecular targets of compound 1. Probe 3 and its improved analogs are expected to join a growing list of ABPP probes that have made important contributions to not only the studies of biochemical and cellular functions but also discovery of selective inhibitors of protein targets.
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware Street S.E., Minneapolis, MN 55455, USA.
authors.forename: Teng
authors.initials: T
authors.lastname: Ai
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware Street S.E., Minneapolis, MN 55455, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Qiu
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware Street S.E., Minneapolis, MN 55455, USA.
authors.forename: Jiashu
authors.initials: J
authors.lastname: Xie
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware Street S.E., Minneapolis, MN 55455, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Geraghty
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware Street S.E., Minneapolis, MN 55455, USA. Electronic address: chenx462@umn.edu.
authors.forename: Liqiang
authors.initials: L
authors.lastname: Chen
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002934:Cinnamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015335:Molecular Probes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D012367:RNA, Viral / Q000235:genetics; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D002934:Cinnamates; D006877:Hydroxamic Acids; D015335:Molecular Probes; D012367:RNA, Viral
keywords: Activity-based protein profiling; Benzothiophene; Cinnamic hydroxamic acid; Hepatitis C virus (HCV); Histone deacetylase; Hydroxamic acid; Matrix metalloproteinases