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)

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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

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Type A Botulinum Toxins
Neurotoxins
Libraries
Peptide Hydrolases
Derivatives
Light
Botulism
Poisons
Poisoning
Inhibitory Concentration 50
Neurons
Rats
Assays
Proteins
betulin
Therapeutics

Keywords

  • betulin derivatives
  • botulinum neurotoxin
  • protease inhibitor

Cite this

Silhár, P., Alakurtti, S., Capková, K., Xiaochuan, F., Shoemaker, C. B., Yli-Kauhaluoma, J., & Janda, K. D. (2011). Synthesis and evaluation of library of betulin derivatives against the botulinum neurotoxin A protease. Bioorganic and Medicinal Chemistry Letters, 21(8), 2229-2231. https://doi.org/10.1016/j.bmcl.2011.02.115
Silhár, Peter ; Alakurtti, Sami ; Capková, Katerina ; Xiaochuan, Feng ; Shoemaker, Charles B. ; Yli-Kauhaluoma, Jari ; Janda, Kim D. / Synthesis and evaluation of library of betulin derivatives against the botulinum neurotoxin A protease. In: Bioorganic and Medicinal Chemistry Letters. 2011 ; Vol. 21, No. 8. pp. 2229-2231.
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Silhár, P, Alakurtti, S, Capková, K, Xiaochuan, F, Shoemaker, CB, Yli-Kauhaluoma, J & Janda, KD 2011, 'Synthesis and evaluation of library of betulin derivatives against the botulinum neurotoxin A protease', Bioorganic and Medicinal Chemistry Letters, vol. 21, no. 8, pp. 2229-2231. https://doi.org/10.1016/j.bmcl.2011.02.115

Synthesis and evaluation of library of betulin derivatives against the botulinum neurotoxin A protease. / Silhár, Peter; Alakurtti, Sami; Capková, Katerina; Xiaochuan, Feng; Shoemaker, Charles B.; Yli-Kauhaluoma, Jari (Corresponding Author); Janda, Kim D. (Corresponding Author).

In: Bioorganic and Medicinal Chemistry Letters, Vol. 21, No. 8, 2011, p. 2229-2231.

Research output: Contribution to journalArticleScientificpeer-review

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