The Interplay of Disulfide Bonds, α-Helicity, and Hydrophobic Interactions Leads to Ultrahigh Proteolytic Stability of Peptides
The Interplay of Disulfide Bonds, α-Helicity, and Hydrophobic Interactions Leads to Ultrahigh Proteolytic Stability of Peptides
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二硫键、α-螺旋性和疏水相互作用的相互作用导致肽的超高蛋白水解稳定性
DOI：
10.1021/acs.biomac.5b00567
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发表时间：
2015-08-01
影响因子：
6.2
通讯作者：
Wu, Chuanliu
中科院分区：
文献类型：
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作者：
Chen, Yaqi;Yang, Chaoqiong;Wu, Chuanliu
非共价相互作用对天然多肽和蛋白质稳定性的贡献已得到普遍承认，尽管如何合理地操纵这些相互作用以提高合成多肽的蛋白水解稳定性仍有待探索。在本研究中，通过将多肽可控地二聚成由两个二硫键连接的a-螺旋二聚体，开发了一个提高多肽蛋白水解稳定性的平台。该平台不仅引导多肽走向a-螺旋构象，而且允许控制二聚体多肽之间的界面疏水相互作用。利用RNase A的n端α -螺旋和已知的E3泛素连接酶MDM2（及其同源物MDMX）抑制剂构建的两种模型二聚体体系，深入了解二硫键、α -螺旋和疏水相互作用对增强蛋白水解稳定性的相互作用。结果表明，这三个参数在获得超高蛋白水解抗性方面发挥着重要作用，这一概念可以用于未来肽疗法的开发。通过本研究获得的理解将使该策略能够适用于新的肽，因为所提出的策略对序列排列表现出相当大的耐受性。因此，它似乎有希望方便地制造完全由治疗肽本身组成的前药（即，以二聚体的形式）。
The contribution of noncovalent interactions to the stability of naturally occurring peptides and proteins has been generally acknowledged, though how these can be rationally manipulated to improve the proteolytic stability of synthetic peptides remains to be explored. In this study, a platform to enhance the proteolytic stability of peptides was developed by controllably dimerizing them into a-helical dimers, connected by two disulfide bonds. This platform not only directs peptides toward an a-helical conformation but permits control of the interfacial hydrophobic interactions between the peptides of the dimer. Using two model dimeric systems constructed from the N-terminal alpha-helix of RNase A and known inhibitors for the E3 ubiquitin ligase MDM2 (and its homologue MDMX), a deeper understanding into the interplay of disulfide bonds, alpha-helicity, and hydrophobic interactions on enhanced proteolytic stability was sought out. Results reveal that all three parameters play an important role on attaining ultrahigh proteolytic resistance, a concept that can be exploited for the development of future peptide therapeutics. The understanding gained through this study will enable this strategy to be tailored to new peptides because the proposed strategy displays substantial tolerance to sequence permutation. It thus appears promising for conveniently creating prodrugs composed entirely of the therapeutic peptide itself (i.e., in the form of a dimer).