Synthesis and evaluation of library of betulin derivatives against the botulinum neurotoxin A protease

Peter Silhár, Sami Alakurtti, Katerina Capková, Feng Xiaochuan, Charles B. Shoemaker, Jari Yli-Kauhaluoma (Corresponding Author), Kim D. Janda (Corresponding Author)

    Research output: Contribution to journalArticleScientificpeer-review

    12 Citations (Scopus)

    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 (IC50 <100 μM) were uncovered. Detailed evaluation of inhibition mechanism of three most active compounds revealed a competitive model, with sub-micromolar Ki 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.
    Original languageEnglish
    Pages (from-to)2229-2231
    Number of pages3
    JournalBioorganic and Medicinal Chemistry Letters
    Volume21
    Issue number8
    DOIs
    Publication statusPublished - 2011
    MoE publication typeA1 Journal article-refereed

    Keywords

    • betulin derivatives
    • botulinum neurotoxin
    • protease inhibitor

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