Combinatorial tuning of peptidic drug candidates: high-affinity matriptase inhibitors through incremental structure-guided optimization
Combinatorial tuning of peptidic drug candidates: high-affinity matriptase inhibitors through incremental structure-guided optimization
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DOI：
10.1039/c3ob27469a
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发表时间：
2013-01-01
影响因子：
3.2
通讯作者：
Kolmar, Harald
中科院分区：
文献类型：
--
作者：
Fittler, Heiko;Avrutina, Olga;Kolmar, Harald
在此，我们报告了一种方便的策略，用于开发基于向日葵胰蛋白酶抑制剂-1（SFTI-1[1，14]）的单环变体的胰蛋白酶样丝氨酸蛋白酶间质蛋白酶的新型高效肽抑制剂。我们筛选了具有母体肽的增量修饰的SFTI-1[1，14]变体，以获得有益的结合特性。该化合物库包括6种肽和16种含三唑的肽模拟物，通过结构指导的合理设计建立，并使用采用“铜点击”化学的发散策略合成。将最有利的氨基酸取代组合在一个框架中，产生有效的SFTI-1衍生的间质蛋白酶抑制剂-1（SFTI-1）和具有个位数纳摩尔抑制常数的截短的十二肽变体（SFTI-2）。计算机模拟研究表明，与亲本肽相比，间质蛋白酶亲和力的提高是由于在碱性抑制剂侧链和靶酶表面上的酸性残基之间成功建立了额外的有利质子供体-受体相互作用。在接近生理学pH下，SST-I和SST-2是药学相关蛋白酶间质蛋白酶的有效抑制剂，因此可以在治疗或诊断中找到应用。
Herein we report a convenient strategy for the development of novel, highly-potent peptidic inhibitors of the trypsin-like serine protease matriptase based on the monocyclic variant of the sunflower trypsin inihibitor-1 (SFTI-1[1,14]). We screened SFTI-1[1,14] variants possessing incremental modifications of the parent peptide for beneficial binding properties. This compound library comprising 6 peptides and 16 triazole-containing peptidomimetics was established via structure-guided rational design and synthesized using a divergent strategy employing "copper-click" chemistry. The most favorable amino acid substitutions were combined in one framework yielding potent SFTI-1-derived matriptase inhibitor-1 (SDMI-1) and the truncated dodecapeptide variant (SDMI-2) with single-digit nanomolar inhibition constants. In silico studies indicated that the improved matriptase affinity compared to the parent peptide is caused by the successful establishment of additional favorable proton donor-acceptor interactions between basic inhibitor side chains and acidic residues on the surface of the target enzyme. SDMI-1 and 2 are potent inhibitors of the pharmaceutically relevant protease matriptase at a near physiological pH and, thus, may find applications in therapy or diagnostics.