Synthesis and evaluation of library of betulin derivatives against the botulinum neurotoxin A protease.
Basic Information
ID: ALA1759928
Journal: Bioorg Med Chem Lett
Title: Synthesis and evaluation of library of betulin derivatives against the botulinum neurotoxin A protease.
Authors: Šilhár P, Alakurtti S, Čapková K, Xiaochuan F, Shoemaker CB, Yli-Kauhaluoma J, Janda KD.
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.
CiteXplore: 21421315
DOI: 10.1016/j.bmcl.2011.02.115
Patent ID: ┄