In situ click chemistry generation of cyclooxygenase-2 inhibitors.
In situ click chemistry generation of cyclooxygenase-2 inhibitors.
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DOI：
10.1038/s41467-016-0009-6
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发表时间：
2017-02-23
影响因子：
16.6
通讯作者：
Wuest F
中科院分区：
文献类型：
--
作者：
Bhardwaj A;Kaur J;Wuest M;Wuest F
环氧合酶-2同工酶是一种很有前途的抗炎药物靶点，该酶的过度表达也与多种癌症和神经退行性疾病有关。诱导型环氧合酶-2和管家型环氧合酶-1异构体之间的氨基酸序列和结构相似性对设计选择性环氧合酶-2抑制剂提出了重大挑战。在此，我们描述了环氧合酶-2活性位点作为反应容器用于原位生成其自身的高度特异性抑制剂的用途。多组分竞争性结合研究证实，环氧合酶-2同工酶可以明智地选择最合适的化学构件从一个池的化学品，以建立自己的高效抑制剂。在此，使用动力学靶向合成，也称为原位点击化学，我们描述了两个高度有效的和选择性的环氧合酶-2同工酶抑制剂的发现。这两种新型小分子的体内抗炎活性显著高于广泛使用的选择性环氧合酶-2抑制剂。传统的炎症和疼痛缓解药物靶向环氧合酶1和2（考克斯-1和考克斯-2），导致严重的副作用。在这里，作者使用原位点击化学来开发具有高体内抗炎活性的考克斯-2特异性抑制剂。
Cyclooxygenase-2 isozyme is a promising anti-inflammatory drug target, and overexpression of this enzyme is also associated with several cancers and neurodegenerative diseases. The amino-acid sequence and structural similarity between inducible cyclooxygenase-2 and housekeeping cyclooxygenase-1 isoforms present a significant challenge to design selective cyclooxygenase-2 inhibitors. Herein, we describe the use of the cyclooxygenase-2 active site as a reaction vessel for the in situ generation of its own highly specific inhibitors. Multi-component competitive-binding studies confirmed that the cyclooxygenase-2 isozyme can judiciously select most appropriate chemical building blocks from a pool of chemicals to build its own highly potent inhibitor. Herein, with the use of kinetic target-guided synthesis, also termed as in situ click chemistry, we describe the discovery of two highly potent and selective cyclooxygenase-2 isozyme inhibitors. The in vivo anti-inflammatory activity of these two novel small molecules is significantly higher than that of widely used selective cyclooxygenase-2 inhibitors. Traditional inflammation and pain relief drugs target both cyclooxygenase 1 and 2 (COX-1 and COX-2), causing severe side effects. Here, the authors use in situ click chemistry to develop COX-2 specific inhibitors with high in vivo anti-inflammatory activity.