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Chitinase inhibitors: Extraction of the active framework from natural argifin and use of in situ click chemistry

Academic Article
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Overview

authors

  • Hirose, T.
  • Sunazuka, T.
  • Sugawara, A.
  • Endo, A.
  • Iguchi, K.
  • Yamamoto, T.
  • Ui, H.
  • Shiomi, K.
  • Watanabe, T.
  • Sharpless, K. Barry
  • Omura, S.

publication date

  • May 2009

journal

  • Journal of Antibiotics  Journal

abstract

  • In situ click chemistry is a target-guided synthesis technique for discovering potent protein ligands by assembling azides and alkynes into triazoles inside the affinity site of a target protein. We report the rapid discovery of a new and potent inhibitor of bacterial chitinases by the use of in situ click chemistry. We observed a target-templated formation of a potent triazole inhibitor of the chitinase-catalyzed chitin hydrolysis, through in situ click chemistry between a biologically active azide-containing scaffold and structurally unrelated alkyne fragments. Chitinase inhibitors have chemotherapeutic potential as fungicides, pesticides and antiasthmatics. Argifin, which has been isolated and characterized as a cyclopentapeptide natural product by our research group, shows strong inhibitory activity against chitinases. As a result of our efforts at developing a chitinase inhibitor from an azide-bearing argifin fragment and the application of the chitinase template and a library of alkynes, we rapidly obtained a very potent and new 1,5-disubstituted triazole inhibitor against Serratia marcescens chitinase (SmChi) B. The new inhibitor expressed 300-fold increase in the inhibitory activity against SmChiB compared with that of argifin. To the best of our knowledge, our finding of an enzyme-made 1,5-disubstituted triazole, using in situ click chemistry is the second example reported in the literature.

subject areas

  • Azides
  • Chitinase
  • Cyclization
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors
  • Mass Spectrometry
  • Peptides, Cyclic
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spectrophotometry, Infrared
  • Triazoles
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Research

keywords

  • argifin
  • chitinase
  • in situ click chemistry
  • target-guided synthesis
  • triazole
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Identity

International Standard Serial Number (ISSN)

  • 0021-8820

Digital Object Identifier (DOI)

  • 10.1038/ja.2009.28

PubMed ID

  • 19329983
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Additional Document Info

start page

  • 277

end page

  • 282

volume

  • 62

issue

  • 5

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