title: Structure-Activity Relationship of Semicarbazone EGA Furnishes Photoaffinity Inhibitors of Anthrax Toxin Cellular Entry.
abstract: EGA, 1, prevents the entry of multiple viruses and bacterial toxins into mammalian cells by inhibiting vesicular trafficking. The cellular target of 1 is unknown, and a structure-activity relationship study was conducted in order to develop a strategy for target identification. A compound with midnanomolar potency was identified (2), and three photoaffinity labels were synthesized (3-5). For this series, the expected photochemistry of the phenyl azide moiety is a more important factor than the IC50 of the photoprobe in obtaining a successful photolabeling event. While 3 was the most effective reversible inhibitor of the series, it provided no protection to cells against anthrax lethal toxin (LT) following UV irradiation. Conversely, 5, which possessed weak bioactivity in the standard assay, conferred robust irreversible protection vs LT to cells upon UV photolysis.
authors.affiliation: California NanoSystems Institute, Department of Chemistry and Biochemistry, Department of Microbiology, Immunology and Molecular Genetics, University of California , Los Angeles, Los Angeles, California 90095, United States.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Jung
authors.affiliation: California NanoSystems Institute, Department of Chemistry and Biochemistry, Department of Microbiology, Immunology and Molecular Genetics, University of California , Los Angeles, Los Angeles, California 90095, United States.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Chamberlain
authors.affiliation: California NanoSystems Institute, Department of Chemistry and Biochemistry, Department of Microbiology, Immunology and Molecular Genetics, University of California , Los Angeles, Los Angeles, California 90095, United States.
authors.forename: Chi-Lee C
authors.initials: CL
authors.lastname: Ho
authors.affiliation: California NanoSystems Institute, Department of Chemistry and Biochemistry, Department of Microbiology, Immunology and Molecular Genetics, University of California , Los Angeles, Los Angeles, California 90095, United States.
authors.forename: Eugene J
authors.initials: EJ
authors.lastname: Gillespie
authors.affiliation: California NanoSystems Institute, Department of Chemistry and Biochemistry, Department of Microbiology, Immunology and Molecular Genetics, University of California , Los Angeles, Los Angeles, California 90095, United States.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Bradley
keywords: Photoaffinity labeling; anthrax lethal toxin; aryl azide; endosomal trafficking; semicarbazone