Mechanism-based inhibitors of serine proteases with high selectivity through optimization of S' subsite binding.
Mechanism-based inhibitors of serine proteases with high selectivity through optimization of S' subsite binding.
复制标题
通过优化 S 亚位点结合，具有高选择性的基于机制的丝氨酸蛋白酶抑制剂。
DOI：
10.1016/j.bmc.2009.04.011
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发表时间：
2009
影响因子：
3.5
通讯作者：
Groutas,WilliamC
中科院分区：
文献类型：
--
作者：
Li,Yi;Dou,Dengfeng;He,Guijia;Lushington,GeraldH;Groutas,WilliamC
设计合成了一系列与丝氨酸蛋白酶S′亚位点相互作用的抑制剂，并研究了它们对丝氨酸蛋白酶HNE和蛋白酶3（PR 3）的抑制活性。发现这些化合物是HNE的时间依赖性抑制剂，并且对PR 3没有任何抑制活性。结果表明，高选择性的丝氨酸蛋白酶抑制剂的主要底物特异性和活性位点是相似的，可以通过利用其S′亚位点的差异来鉴定。最好的抑制剂（化合物16）的kinact/KI值为4580 M − 1 s −1。
A series of mechanism-based inhibitors designed to interact with the S′ subsites of serine proteases was synthesized and their inhibitory activity toward the closely-related serine proteases human neutrophil elastase (HNE) and proteinase 3 (PR 3) was investigated. The compounds were found to be time-dependent inhibitors of HNE and were devoid of any inhibitory activity toward PR 3. The results suggest that highly selective inhibitors of serine proteases whose primary substrate specificity and active sites are similar can be identified by exploiting differences in their S′ subsites. The best inhibitor (compound 16) had a kinact/KIvalue of 4580M−1s−1.