The Identification and Biochemical Characterization of Drug-like Compounds That Inhibit Botulinum Neurotoxin Serotype A Endopeptidase Activity

Overview

Journal Toxicon

Specialty Toxicology

Date 2009 Dec 17

PMID 20003913

Citations 12

Authors

Shuowei Cai

Paul Lindo

Jong-Beak Park

Kruti Vasa

Bal Ram Singh

Affiliations

Soon will be listed here.

Abstract

A robust, high-throughput, two-tiered assay for screening small molecule inhibitors against botulinum neurotoxin serotype A was developed and employed to screen 16,544 compounds. Thirty-four compounds were identified as potent hits employing the first-tier assay. Subsequently, nine were confirmed as actives by our second-tier confirmatory assay. Of these, one displayed potent inhibitory efficacy, possessing an IC(50)=16 microM (+/-1.6 microM) in our in vitro assay. This inhibitor (0831-1035) is highly water-soluble, and possesses an IC(50)=47 microM (+/-7.0 microM) in our primary cell culture assay (with virtually no cytotoxicity up to 500 microM), suggesting that this inhibitor is a good candidate for further development as a therapeutic countermeasure to treat botulism resulting from botulinum neurotoxin serotype A intoxication. An enzyme kinetics study indicated that this inhibitor exhibits mixed non-competitive inhibition, with a K(I)=9 microM.

Citing Articles

Clostridial Neurotoxins: Structure, Function and Implications to Other Bacterial Toxins.

Cai S, Kumar R, Singh B Microorganisms. 2021; 9(11).

PMID: 34835332 PMC: 8618262. DOI: 10.3390/microorganisms9112206.

Natural Compounds and Their Analogues as Potent Antidotes against the Most Poisonous Bacterial Toxin.

Patel K, Cai S, Adler M, Singh B, Parmar V, Singh B Appl Environ Microbiol. 2018; 84(24).

PMID: 30389764 PMC: 6275346. DOI: 10.1128/AEM.01280-18.

A Novel Surface Plasmon Resonance Biosensor for the Rapid Detection of Botulinum Neurotoxins.

Patel K, Halevi S, Melman P, Schwartz J, Cai S, Singh B Biosensors (Basel). 2017; 7(3).

PMID: 28783115 PMC: 5618038. DOI: 10.3390/bios7030032.

Selection of RNA Aptamers Against Botulinum Neurotoxin Type A Light Chain Through a Non-Radioactive Approach.

Chang T, Janardhanan P, Mello C, Singh B, Cai S Appl Biochem Biotechnol. 2016; 180(1):10-25.

PMID: 27085355 PMC: 5010959. DOI: 10.1007/s12010-016-2081-0.

Effect of botulinum neurotoxin type A (BoNTA) on the morphology and viability of 3T3 murine fibroblasts.

Bandala C, Teran-Melo J, Anaya-Ruiz M, Mejia-Barradas C, Dominguez-Rubio R, De la Garza-Montano P Int J Clin Exp Pathol. 2015; 8(8):9458-62.

PMID: 26464704 PMC: 4583936.

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