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High-Throughput Screening Uncovers Novel Botulinum Neurotoxin Inhibitor Chemotypes

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Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
§ Fox Chase Chemical Diversity Center, 3805 Old Easton Road, Doylestown, Pennsylvania 18902, United States
*Phone: +1 (858) 784-2522. E-mail: [email protected]
Cite this: ACS Comb. Sci. 2016, 18, 8, 461–474
Publication Date (Web):June 17, 2016
https://doi.org/10.1021/acscombsci.6b00033
Copyright © 2016 American Chemical Society

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    Abstract

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    Botulism is caused by potent and specific bacterial neurotoxins that infect host neurons and block neurotransmitter release. Treatment for botulism is limited to administration of an antitoxin within a short time window, before the toxin enters neurons. Alternatively, current botulism drug development targets the toxin light chain, which is a zinc-dependent metalloprotease that is delivered into neurons and mediates long-term pathology. Several groups have identified inhibitory small molecules, peptides, or aptamers, although no molecule has advanced to the clinic due to a lack of efficacy in advanced models. Here we used a homogeneous high-throughput enzyme assay to screen three libraries of drug-like small molecules for new chemotypes that modulate recombinant botulinum neurotoxin light chain activity. High-throughput screening of 97088 compounds identified numerous small molecules that activate or inhibit metalloprotease activity. We describe four major classes of inhibitory compounds identified, detail their structure–activity relationships, and assess their relative inhibitory potency. A previously unreported chemotype in any context of enzyme inhibition is described with potent submicromolar inhibition (Ki = 200–300 nM). Additional detailed kinetic analyses and cellular cytotoxicity assays indicate the best compound from this series is a competitive inhibitor with cytotoxicity values around 4–5 μM. Given the potency and drug-like character of these lead compounds, further studies, including cellular activity assays and DMPK analysis, are justified.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscombsci.6b00033.

    • Figures showing representative dose–response curves for the 3 lead benzimidazole compounds 45, 47, and 90 in the SNAPtide FRET-based LC/A enzyme assay, off-target zinc metalloprotease activity for compounds 4, 33, 37, 47, and 90 with MMP-1, MMP-12, and thermolysin, murine neuroblastoma cytotoxicity data for compounds 45 and 90 and tables showing the potentially reactive moieties and problematic structures that were filtered for during the initial library generation, structures of inactive spiro(indol-thiadiazole) compounds, structures of inactive 8-sulfonamidoquinoline compounds, and structures of inactive benzimidazole pyrazolopiperidinone compounds (PDF)

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    Cited By

    This article is cited by 2 publications.

    1. Ritika Chauhan, Vinita Chauhan, Priyanka Sonkar, Ram Kumar Dhaked. Identification of Inhibitors against Botulinum Neurotoxins: 8-Hydroxyquinolines Hold Promise. Mini-Reviews in Medicinal Chemistry 2019, 19 (20) , 1694-1706. https://doi.org/10.2174/1389557519666190906120228
    2. Ritika Chauhan, Vinita Chauhan, Priyanka Sonkar, Manorama Vimal, Ram Kumar Dhaked. Targeted 8-hydroxyquinoline fragment based small molecule drug discovery against neglected botulinum neurotoxin type F. Bioorganic Chemistry 2019, 92 , 103297. https://doi.org/10.1016/j.bioorg.2019.103297