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首页> 外文期刊>RSC Advances >Comparison of hydrocarbon-and lactam-bridged cyclic peptides as dimerization inhibitors of Leishmania infantum trypanothione reductase
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Comparison of hydrocarbon-and lactam-bridged cyclic peptides as dimerization inhibitors of Leishmania infantum trypanothione reductase

机译：烃和内酰胺桥循环肽的比较作为Leishmania幼稚蛋白硫酰硫氧皂酶还原酶二聚化抑制剂

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摘要

All-hydrocarbon and lactam-bridged staples linking amino acid side-chains have been used to stabilize the a-helical motif in short 13-mer peptides that target critical protein-protein interactions at the dimerization interface of Leishmania infantum trypanothione reductase (Li-TryR). The design of the best positions for covalent hydrocarbon closure relied on a theoretical prediction of the degree of helicity of the corresponding cyclic peptides in water. Selected (i, i + 4) and (i, i + 7) hydrocarbon-stapled peptides were prepared by using solid-phase synthesis protocols and optimized ring-closing metathesis reactions under microwave conditions. Structural analysis by NMR spectroscopy confirmed high helical contents in aqueous TFE solutions for both types of helix-constrained cyclic peptides. Remarkably, the ability to prevent Li-TryR dimerization was reduced in both (i, i + 4) and (i, i + 7) hydrocarbon stapled peptides but was retained in the corresponding (i, i + 4) Glu-Lys lactam-bridged analogue, which also showed a higher resistance to proteolytic degradation by proteinase K relative to the linear peptide prototype. In silico studies indicated that the introduction of a hydrocarbon staple vs. a lactam bridge likely perturbs critical interactions required for proper binding of the peptide to the Li-TryR monomer.
机译：链接氨基酸侧链的全烃和内酰胺桥钉已被用于稳定A形螺旋基序，以靶向LeishMania Infantum Trypanothione还原酶二聚化界面的关键蛋白质 - 蛋白质相互作用（Li-Tryr ）。共价碳氢化合物封闭件的最佳位置的设计依赖于水中相应环状肽的螺旋度的理论预测。通过使用固相合成方案和微波条件下的优化的闭合复分解反应来制备所选（I，I + 4）和（I，I + 7）烃类饮料肽。 NMR光谱的结构分析证实了两种类型的螺旋约束循环肽的TFE水溶液中的高螺旋含量。值得注意的是，在（I，I + 4）和（I，I + 7）烃吻合肽中，预防Li-Tryr二聚化的能力降低，但保留在相应的（I，I + 4）Glu-Lys内酰胺 - 桥接类似物，其还显示出相对于线性肽原型的蛋白酶K的蛋白水解降解较高的抗性。在硅研究中，表明烃尖端与内酰胺桥的引入可能对肽与Li-tryr单体相当合适的关键相互作用。

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