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Design of a Short Thermally Stable α-Helix Embedded in a Macrocycle

Overview
Journal Chembiochem
Specialty Biochemistry
Date 2018 Feb 9
PMID 29417711
Citations 10
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Abstract

Although helices play key roles in peptide-protein and protein-protein interactions, the helical conformation is generally unstable for short peptides (10-15 residues) in aqueous solution in the absence of their binding partners. Thus, stabilizing the helical conformation of peptides can lead to increases in binding potency, specificity, and stability towards proteolytic degradation. Helices have been successfully stabilized by introducing side chain-to-side chain crosslinks within the central portion of the helix. However, this approach leaves the ends of the helix free, thus leading to fraying and exposure of the non-hydrogen-bonded amide groups to solvent. Here, we develop a "capped-strapped" peptide strategy to stabilize helices by embedding the entire length of the helix within a macrocycle, which also includes a semirigid organic template as well as end-capping interactions. We have designed a ten-residue capped-strapped helical peptide that behaves like a miniprotein, with a cooperative thermal unfolding transition and T ≈70 °C, unprecedented for helical peptides of this length. The NMR structure determination confirmed the design, and X-ray crystallography revealed a novel quaternary structure with implications for foldamer design.

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References
1.
Phillips C, Roberts L, Schade M, Bazin R, Bent A, Davies N . Design and structure of stapled peptides binding to estrogen receptors. J Am Chem Soc. 2011; 133(25):9696-9. DOI: 10.1021/ja202946k. View

2.
Spokoyny A, Zou Y, Ling J, Yu H, Lin Y, Pentelute B . A perfluoroaryl-cysteine S(N)Ar chemistry approach to unprotected peptide stapling. J Am Chem Soc. 2013; 135(16):5946-9. PMC: 3675880. DOI: 10.1021/ja400119t. View

3.
Johnson L, Gellman S . α-Helix mimicry with α/β-peptides. Methods Enzymol. 2013; 523:407-29. PMC: 3928965. DOI: 10.1016/B978-0-12-394292-0.00019-9. View

4.
Chin J, Schepartz A . Concerted evolution of structure and function in a miniature protein. J Am Chem Soc. 2001; 123(12):2929-30. PMC: 2926943. DOI: 10.1021/ja0056668. View

5.
Patgiri A, Jochim A, Arora P . A hydrogen bond surrogate approach for stabilization of short peptide sequences in alpha-helical conformation. Acc Chem Res. 2008; 41(10):1289-300. PMC: 7189275. DOI: 10.1021/ar700264k. View