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