Stabilization of peptides against proteolysis through disulfide-bridged conjugation with synthetic aromatics
Stabilization of peptides against proteolysis through disulfide-bridged conjugation with synthetic aromatics
复制标题
通过二硫键与合成芳族化合物缀合，稳定肽，防止蛋白水解
DOI：
10.1039/c6ob02786e
复制
发表时间：
2017-02-28
影响因子：
3.2
通讯作者：
Wu, Chuanliu
中科院分区：
文献类型：
--
作者：
Chen, Yaqi;Li, Tao;Wu, Chuanliu
肽类化合物是一种对生物大分子具有高度亲和性和特异性的分子支架材料。然而，它们固有的蛋白水解不稳定性显著阻碍了它们的生物学应用。非常需要基于非共价相互作用的策略，其可以稳定肽对抗蛋白水解消化，而不需要对序列进行大量操作或使用非天然残基。在这项工作中，我们开发了一种通用的，方便的，有效的策略，稳定肽对蛋白水解，这涉及肽中的芳香族氨基酸残基和合成的缺电子芳香族化合物（NDI）之间的非共价p-p相互作用，以及空间位阻（从庞大的NDI部分）的含义，和肽α-螺旋度的增强。这种策略在概念上与传统的成熟的肽稳定化共价方法是互补的，因此有希望与后者结合使用，以避免肽的蛋白水解不稳定性问题。我们设想，这项研究将提供宝贵的指导方针，设计和合成的有机分子-肽杂交与显着改善蛋白水解抗性，并有利于肽治疗和探针的开发。
Peptides have been promising molecular scaffolds for the development of potential therapeutics with high affinity and specificity to biomacromolecules. However, their inherent proteolytic instability significantly hampers their biological applications. Strategies that can stabilize peptides against proteolytic digestion on the basis of noncovalent interactions-without extensive manipulation of the sequence or use of unnatural residues-are greatly desired. In this work, we developed a general, convenient, and efficient strategy for the stabilization of peptides against proteolysis, which involves noncovalent p-p interactions between aromatic amino acid residues in peptides and synthetic electron-deficient aromatics (NDI), together with the implication of steric hindrance (from the bulky NDI moiety), and the enhancement of peptide alpha-helicity. This strategy is complementary in concept to the conventional well-established covalent approaches for peptide stabilization, and is thus promising for being utilized, in combination with the latter ones, to circumvent the problem of proteolytic instability of peptides. We envisioned that this study should provide invaluable guidelines to the design and synthesis of organic molecule-peptide hybrids with significantly improved proteolytic resistance, and benefit the development of peptide therapeutics and probes.