Examination of α-exosite inhibitors against Botulinum neurotoxin A protease through structure-activity relationship studies of chicoric acid

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:27

Article

Xue, Song^1,2,3  Seki, Hajime^1,2,3  Remes, Marek^1,2,3,5,6  Silhar, Peter^1,2,3  Janda, Kim^1,2,3,4 

[1] Scripps Res Inst, Dept Chem, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA

[2] Scripps Res Inst, Skaggs Inst Chem Biol, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA

[3] Scripps Res Inst, Dept Immunol, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA

[4] Scripps Res Inst, Worm Inst Res Med, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA

[5] Brno Univ Technol, Cent European Inst Technol, Tech 11 3058 10, CZ-61600 Brno, Czech Republic

[6] Mendel Univ Brno, Dept Chem & Biochem, Zemedelska 1, CZ-961300 Brno, Czech Republic

关键词: Botulinum neurotoxins;    Chicoric acid;    Structure-activity relationship;   

DOI  :  10.1016/j.bmcl.2017.10.021

来源: Elsevier

【 摘 要 】

Botulinum neurotoxins (BoNT) are among the most toxic known substances and currently there are no effective treatments for intraneuronal BoNT intoxication. Chicoric acid (ChA) was previously reported as a BoNT/A inhibitor that binds to the enzyme's alpha-exosite. Herein, we report the synthesis and structure-activity relationships (SARs) of a series of ChA derivatives, which revealed essential binding interactions between ChA and BoNT/A. Moreover, several ChA-based inhibitors with improved potency against the BoNT/A were discovered. (C) 2017 Elsevier Ltd. All rights reserved.

【 授权许可】

Free