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首页> 外文期刊>Chemistry: A European journal >Conformationally Constrained Peptidomimetics as Inhibitors of the Protein Arginine Methyl Transferases
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Conformationally Constrained Peptidomimetics as Inhibitors of the Protein Arginine Methyl Transferases

机译：构象约束肽模拟物作为蛋白质精氨酸甲基转移酶的抑制剂

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摘要

Protein arginine N-methyl transferases (PRMTs) belong to a family of enzymes that modulate the epigenetic code through modifications of histones. In the present study, peptides emerging from a phage display screening were modified in the search for PRMT inhibitors through substitution with non-proteinogenic amino acids, N-alkylation of the peptide backbone, and incorporation of constrained dipeptide mimics. One of the modified peptides (23) showed an increased inhibitory activity towards several PRMTs in the low mm range and the conformational preference of this peptide was investigated and compared with the original hit using circular dichroism and NMR spectroscopy. Introducing two constrained tryptophan residue mimics (L-Aia) spaced by a single amino acid was found to induce a unique turn structure stabilized by a hydrogen bond and aromatic pi-stacking interaction between the two L-Aia residues.
机译：蛋白质精氨酸N-甲基转移酶（PRMT）属于通过修饰组蛋白来调节表观遗传密码的酶家族。在本研究中，通过用非蛋白原性氨基酸取代，肽主链的N-烷基化以及结合受约束的二肽模拟物，修饰了从噬菌体展示筛选中出现的肽，以寻找PRMT抑制剂。一种修饰的肽（23）在低mm范围内显示出对几种PRMT的抑制活性增强，并且研究了该肽的构象偏好，并使用圆二色性和NMR光谱将其与原始命中进行了比较。发现引入两个受约束的色氨酸残基模拟物（L-Aia），它们之间用一个氨基酸隔开，可以诱导通过两个L-Aia残基之间的氢键和芳香族pi堆积相互作用稳定的独特转向结构。

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