伪/尾-Peptide Foldamers Targeting Intracellular Protein鈥揚rotein Interactions with Activity in Living Cells

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• 作者：James W. Checco ; Erinna F. Lee ; Marco Evangelista ; Nerida J. Sleebs ; Kelly Rogers ; Anne Pettikiriarachchi ; Nadia J. Kershaw ; Geoffrey A. Eddinger ; David G. Belair ; Julia L. Wilson ; Chelcie H. Eller ; Ronald T. Raines ; William L. Murphy ; Brian J. Smith ; Samuel H. Gellman ; W. Douglas Fairlie
• 刊名：Journal of the American Chemical Society
• 出版年：2015
• 出版时间：September 9, 2015
• 年：2015
• 卷：137
• 期：35
• 页码：11365-11375
• 全文大小：640K
• ISSN：1520-5126

文摘

Peptides can be developed as effective antagonists of protein鈥損rotein interactions, but conventional peptides (i.e., oligomers of l-伪-amino acids) suffer from significant limitations in vivo. Short half-lives due to rapid proteolytic degradation and an inability to cross cell membranes often preclude biological applications of peptides. Oligomers that contain both 伪- and 尾-amino acid residues (鈥溛?尾-peptides鈥? manifest decreased susceptibility to proteolytic degradation, and when properly designed these unnatural oligomers can mimic the protein-recognition properties of analogous 鈥溛?peptides鈥? This report documents an extension of the 伪/尾-peptide approach to target intracellular protein鈥損rotein interactions. Specifically, we have generated 伪/尾-peptides based on a 鈥渟tapled鈥?Bim BH3 伪-peptide, which contains a hydrocarbon cross-link to enhance 伪-helix stability. We show that a stapled 伪/尾-peptide can structurally and functionally mimic the parent stapled 伪-peptide in its ability to enter certain types of cells and block protein鈥損rotein interactions associated with apoptotic signaling. However, the 伪/尾-peptide is nearly 100-fold more resistant to proteolysis than is the parent stapled 伪-peptide. These results show that backbone modification, a strategy that has received relatively little attention in terms of peptide engineering for biomedical applications, can be combined with more commonly deployed peripheral modifications such as side chain cross-linking to produce synergistic benefits.