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.
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Acknowledgements
This work was supported by the Grant of the 21st Century COE Program, Ministry of Education Culture, Sports, Science and Technology. We also thank Ms A Nakagawa, Ms N Sato and Dr K Nagai for various instrumental analyses.
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Hirose, T., Sunazuka, T., Sugawara, A. et al. Chitinase inhibitors: extraction of the active framework from natural argifin and use of in situ click chemistry. J Antibiot 62, 277–282 (2009). https://doi.org/10.1038/ja.2009.28
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DOI: https://doi.org/10.1038/ja.2009.28
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