title: Synthesis and evaluation of library of betulin derivatives against the botulinum neurotoxin A protease.
abstract: Botulinum neurotoxins (BoNTs) are the most toxic proteins currently known. Current treatments for botulinum poisoning are all protein based with a limited window of opportunity. Inhibition of the BoNT light chain protease (LC) has emerged as a new therapeutic strategy for the treatment of botulism as it may provide an effective post-exposure remedy. As such, a small library of 40 betulin derivatives was synthesized and screened against the light chain of BoNT serotype A (LC/A); five positive hits (IC(50) <100 μM) were uncovered. Detailed evaluation of inhibition mechanism of three most active compounds revealed a competitive model, with sub-micromolar K(i) value for the best inhibitor (7). Unfortunately, an in vitro cell-based assay did not show any protection of rat cerebellar neurons against BoNT/A intoxication by 7.
authors.affiliation: Department of Chemistry, Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Šilhár
authors.forename: Sami
authors.initials: S
authors.lastname: Alakurtti
authors.forename: Kateřina
authors.initials: K
authors.lastname: Čapková
authors.forename: Feng
authors.initials: F
authors.lastname: Xiaochuan
authors.forename: Charles B
authors.initials: CB
authors.lastname: Shoemaker
authors.forename: Jari
authors.initials: J
authors.lastname: Yli-Kauhaluoma
authors.forename: Kim D
authors.initials: KD
authors.lastname: Janda
mesh_terms: D000818:Animals; D001905:Botulinum Toxins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013386:Succinates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014315:Triterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D011480:Protease Inhibitors; D054852:Small Molecule Libraries; D013386:Succinates; D014315:Triterpenes; D001905:Botulinum Toxins; D019274:Botulinum Toxins, Type A