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Literature DB >> 29050781

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

Song Xue¹, Hajime Seki¹, Marek Remes¹, Peter Šilhár¹, Kim Janda².

Abstract

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 α-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.

Entities: Chemical Disease Gene Species

Keywords: Botulinum neurotoxins; Chicoric acid; Structure-activity relationship

Mesh：

Substances：

Year: 2017 PMID： 29050781 PMCID： PMC5667901 DOI： 10.1016/j.bmcl.2017.10.021

Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823

11 in total

1. Diagnosis and treatment of botulism: a century later, clinical suspicion remains the cornerstone.

Authors: Jeremy Sobel
Journal: Clin Infect Dis Date: 2009-06-15 Impact factor: 9.079

2. Toward the discovery of potent inhibitors of botulinum neurotoxin A: development of a robust LC MS based assay operational from low to subnanomolar enzyme concentrations.

Authors: Katerina Capková; Mark S Hixon; Laura A McAllister; Kim D Janda
Journal: Chem Commun (Camb) Date: 2008-07-03 Impact factor: 6.222

3. Toward the discovery of dual inhibitors for botulinum neurotoxin A: concomitant targeting of endocytosis and light chain protease activity.

Authors: Hajime Seki; Song Xue; Mark S Hixon; Sabine Pellett; Marek Remes; Eric A Johnson; Kim D Janda
Journal: Chem Commun (Camb) Date: 2015-04-11 Impact factor: 6.222

4. Substrate recognition strategy for botulinum neurotoxin serotype A.

Authors: Mark A Breidenbach; Axel T Brunger
Journal: Nature Date: 2004-12-12 Impact factor: 49.962

5. The Yonetani-Theorell graphical method for examining overlapping subsites of enzyme active centers.

Authors: T Yonetani
Journal: Methods Enzymol Date: 1982 Impact factor: 1.600

Review 6. Botulism.

Authors: Jeremy Sobel
Journal: Clin Infect Dis Date: 2005-08-29 Impact factor: 9.079

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

1. Diagnosis and treatment of botulism: a century later, clinical suspicion remains the cornerstone.

2. Toward the discovery of potent inhibitors of botulinum neurotoxin A: development of a robust LC MS based assay operational from low to subnanomolar enzyme concentrations.

3. Toward the discovery of dual inhibitors for botulinum neurotoxin A: concomitant targeting of endocytosis and light chain protease activity.

4. Substrate recognition strategy for botulinum neurotoxin serotype A.

5. The Yonetani-Theorell graphical method for examining overlapping subsites of enzyme active centers.

Review 6. Botulism.

7. Botulinum neurotoxin A protease: discovery of natural product exosite inhibitors.

Review 8. Botulinal neurotoxins: revival of an old killer.

9. SNARE motif and neurotoxins.

10. Probing BoNT/A protease exosites: implications for inhibitor design and light chain longevity.

1. Identification of Slow-Binding Inhibitors of the BoNT/A Protease.