Residue-Based Preorganization of BH3-Derived 伪/尾-Peptides: Modulating Affinity, Selectivity and Proteolytic Susceptibility in 伪-Helix Mimics

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• 作者：Kimberly J. Peterson-Kaufman ; Holly S. Haase ; Melissa D. Boersma ; Erinna F. Lee ; W. Douglas Fairlie ; Samuel H. Gellman
• 刊名：ACS Chemical Biology
• 出版年：2015
• 出版时间：July 17, 2015
• 年：2015
• 卷：10
• 期：7
• 页码：1667-1675
• 全文大小：445K
• ISSN：1554-8937

文摘

We report progress toward a general strategy for mimicking the recognition properties of specific 伪-helices within natural proteins through the use of oligomers that are less susceptible than conventional peptides to proteolysis. The oligomers contain both 伪- and 尾-amino acid residues, with the density of the 尾 subunits low enough that an 伪-helix-like conformation can be adopted but high enough to interfere with protease activity. Previous studies with a different protein-recognition system that suggested ring-constrained 尾 residues can be superior to flexible 尾 residues in terms of maximizing 伪/尾-peptide affinity for a targeted protein surface. Here, we use mimicry of the 18-residue Bim BH3 domain to expand the scope of this strategy. Two significant advances have been achieved. First, we have developed and validated a new ring-constrained 尾 residue that bears an acidic side chain, which complements previously known analogues that are either hydrophobic or basic. Second, we have discovered that placing cyclic 尾 residues at sites that make direct contact with partner proteins can lead to substantial discrimination between structurally homologous binding partners, the proteins Bcl-x_L and Mcl-1. Overall, this study helps to establish that 伪/尾-peptides containing ring-preorganized 尾 residues can reliably provide proteolytically resistant ligands for proteins that naturally evolved to recognize 伪-helical partners.