title: Chitinase inhibitors: extraction of the active framework from natural argifin and use of in situ click chemistry.
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.
authors.affiliation: The Kitasato Institute and Kitasato Institute for Life Science and Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Hirose
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Sunazuka
authors.forename: Akihiro
authors.initials: A
authors.lastname: Sugawara
authors.forename: Ayako
authors.initials: A
authors.lastname: Endo
authors.forename: Kanami
authors.initials: K
authors.lastname: Iguchi
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ui
authors.forename: Kazuro
authors.initials: K
authors.lastname: Shiomi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Watanabe
authors.forename: K Barry
authors.initials: KB
authors.lastname: Sharpless
authors.forename: Satoshi
authors.initials: S
authors.lastname: Omura