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

Tomoyasu Hirose, Toshiaki Sunazuka, Akihiro Sugawara, Ayako Endo, Kanami Iguchi, Tsuyoshi Yamamoto, Hideaki Ui, Kazuro Shiomi, Takeshi Watanabe, K. Barry Sharpless, Satoshi Ömura

Research output: Contribution to journalArticlepeer-review

47 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)277-282
Number of pages6
JournalJournal of Antibiotics
Issue number5
Publication statusPublished - 2009 May
Externally publishedYes


  • Argifin
  • Chitinase
  • In situ click chemistry
  • Target-guided synthesis
  • Triazole

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery


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