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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 ?M) 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.

SUBMITTER: Silhar P

PROVIDER: S-EPMC3070790 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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

Šilhár Peter P Alakurtti Sami S Čapková Kateřina K Xiaochuan Feng F Shoemaker Charles B CB Yli-Kauhaluoma Jari J Janda Kim D KD

Bioorganic & medicinal chemistry letters 20110304 8

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 hit ...[more]

PMID: 21421315

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