Chitinase inhibitors: extraction of the active framework from natural argifin and use of in situ click chemistry
Chitinase inhibitors: extraction of the active framework from natural argifin and use of in situ click chemistry
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DOI：
10.1038/ja.2009.28
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发表时间：
2009-05-01
影响因子：
3.3
通讯作者：
Omura, Satoshi
中科院分区：
文献类型：
--
作者：
Hirose, Tomoyasu;Sunazuka, Toshiaki;Omura, Satoshi
原位点击化学是一种靶向合成技术，用于通过将叠氮化物和炔组装成靶蛋白的亲和位点内的三唑来发现有效的蛋白质配体。我们报告了一种新的和有效的细菌几丁质酶抑制剂的快速发现，通过使用原位点击化学。我们观察到一个有效的三唑抑制剂的几丁质酶催化的几丁质水解，通过原位点击化学之间的生物活性的含叠氮化物的支架和结构无关的炔片段的目标模板形成。几丁质酶抑制剂具有作为杀真菌剂、杀虫剂和抗哮喘药的化学治疗潜力。Argifin是本课题组分离鉴定的一种环戊肽类天然产物，对几丁质酶具有很强的抑制活性。由于我们努力从含叠氮的argifin片段开发几丁质酶抑制剂，并应用几丁质酶模板和炔库，我们迅速获得了一个非常有效的和新的1，5-二取代三唑抑制剂对粘质沙雷氏菌几丁质酶（SmChi）B。与argifin相比，新抑制剂对SmChiB的抑制活性增加了300倍。据我们所知，我们使用原位点击化学发现了酶制1，5-二取代三唑，这是文献中报道的第二个例子。The Journal of Antibiotics（2009）62，277-282; doi：10.1038/ja.2009.28; 2009年3月27日在线发表
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. The Journal of Antibiotics (2009) 62, 277-282; doi:10.1038/ja.2009.28; published online 27 March 2009