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

Peter Šilhár; Sami Alakurtti; Kateřina Čapková; Feng Xiaochuan; Charles B. Shoemaker; Jari Yli-Kauhaluoma; Kim D. Janda

doi:10.1016/j.bmcl.2011.02.115

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

Peter Šilhár, Sami Alakurtti, Kateřina Čapková, Feng Xiaochuan, Charles B. Shoemaker, Jari Yli-Kauhaluoma^*, Kim D. Janda^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Scientific › peer-review

13 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 language	English
Pages (from-to)	2229-2231
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	21
Issue number	8
DOIs	https://doi.org/10.1016/j.bmcl.2011.02.115
Publication status	Published - 2011
MoE publication type	A1 Journal article-refereed

Keywords

betulin derivatives
botulinum neurotoxin
protease inhibitor

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10.1016/j.bmcl.2011.02.115

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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 (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.",

keywords = "betulin derivatives, botulinum neurotoxin, protease inhibitor",

author = "Peter {\v S}ilh{\'a}r and Sami Alakurtti and Kate{\v r}ina {\v C}apkov{\'a} and Feng Xiaochuan and Shoemaker, \{Charles B.\} and Jari Yli-Kauhaluoma and Janda, \{Kim D.\}",

year = "2011",

doi = "10.1016/j.bmcl.2011.02.115",

language = "English",

volume = "21",

pages = "2229--2231",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

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TY - JOUR

T1 - Synthesis and evaluation of library of betulin derivatives against the botulinum neurotoxin A protease

AU - Šilhár, Peter

AU - Alakurtti, Sami

AU - Čapková, Kateřina

AU - Xiaochuan, Feng

AU - Shoemaker, Charles B.

AU - Yli-Kauhaluoma, Jari

AU - Janda, Kim D.

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

KW - betulin derivatives

KW - botulinum neurotoxin

KW - protease inhibitor

U2 - 10.1016/j.bmcl.2011.02.115

DO - 10.1016/j.bmcl.2011.02.115

M3 - Article

SN - 0960-894X

VL - 21

SP - 2229

EP - 2231

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 8

ER -

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

Abstract

Keywords

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