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Identification of a natural product antagonist against the botulinum neurotoxin light chain protease

Academic Article
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Overview

authors

  • Eubanks, L. M.
  • Silhar, P.
  • Salzameda, N. T.
  • Zakhari, J. S.
  • Xiaochuan, F.
  • Barbieri, J. T.
  • Shoemaker, C. B.
  • Hixon, M. S.
  • Janda, Kim

publication date

  • September 2010

journal

  • ACS Medicinal Chemistry Letters  Journal

abstract

  • Botulinum neurotoxins (BoNTs) are the etiological agents responsible for botulism, a disease characterized by peripheral neuromuscular blockade and a characteristic flaccid paralysis of humans. BoNTs are the most lethal known poisons affecting humans and has been recognized as a potential bioterrorist threat. Current treatments for botulinum poisoning are predominately prophylactic in nature relying on passive immunization with antitoxins. Inhibition of the BoNT light chain metalloprotease (LC) has emerged as a new therapeutic strategy for the treatment of botulism that may provide an effective post-exposure remedy. A high-throughput screening effort against the light chain of BoNT serotype A (LC/A) was conducted with the John Hopkins Clinical Compound Library comprised of over 1,500 existing drugs. Lomofungin, a natural product first isolated in the late 1960's, was identified as an inhibitor of LC/A, displaying classical noncompetitive inhibition kinetics with a K(i) of 6.7 ± 0.7 µM. Inhibitor combination studies reveal that lomofungin binding is nonmutually exclusive (synergistic). The inhibition profile of lomofungin has been delineated by the use of both an active site inhibitor, 2,4-dichlorocinnamic hydroxamate, and a noncompetitive inhibitor d-chicoric acid; the mechanistic implications of these observations are discussed. Lastly, cellular efficacy was investigated using a rat primary cell model which demonstrated that lomofungin can protect against SNAP-25 cleavage, the intracellular protein target of LC/A.
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Research

keywords

  • Botulinum neurotoxin
  • high-throughput screening
  • natural product
  • small molecule inhibitor
  • zinc-dependent metalloprotease
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Identity

PubMed Central ID

  • PMC2955888

International Standard Serial Number (ISSN)

  • 1948-5875

Digital Object Identifier (DOI)

  • 10.1021/ml100074s

PubMed ID

  • 20959871
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Additional Document Info

start page

  • 268

end page

  • 272

volume

  • 1

issue

  • 6

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