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Review
. 2008 Dec;12(6):692-7.
doi: 10.1016/j.cbpa.2008.08.019. Epub 2008 Sep 13.

Contemporary strategies for the stabilization of peptides in the alpha-helical conformation

Laura K Henchey  1 , Andrea L Jochim, Paramjit S Arora
Affiliations
Review

Contemporary strategies for the stabilization of peptides in the alpha-helical conformation

Laura K Henchey et al. Curr Opin Chem Biol. 2008 Dec.

Abstract

Herein we review contemporary synthetic and protein design strategies to stabilize the alpha-helical motif in short peptides and miniature proteins. Advances in organometallic catalyst design, specifically for the olefin metathesis reaction, enable the use of hydrocarbon bridges to either crosslink side chains of specific residues or mimic intramolecular hydrogen bonds with carbon-carbon bonds. The resulting hydrocarbon-stapled and hydrogen bond surrogate alpha-helices provide unique synthetic ligands for targeting biomolecules. In the protein design realm, several classes of miniature proteins that display stable helical domains have been engineered and manipulated with powerful in vitro selection technologies to yield libraries of sequences that retain their helical folds. Rational re-design of these scaffolds provide distinctive reagents for the modulation of protein-protein interactions.

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Figures

Figure 1
Figure 1
Stabilized helices and nonnatural helix mimetics: several strategies that stabilize the α-helical conformation in peptides or mimic this domain with nonnatural scaffolds have been described. Recent advances include β-peptide helices, terphenyl helix-mimetics, mini-proteins, peptoid helices, side-chain crosslinked α-helices, and the hydrogen bond surrogate (HBS) derived α-helices. Green circles represent amino acid side chain functionality.
Figure 2
Figure 2
(a) Nucleation of short α-helices by replacement of an N-terminal i and i+4 hydrogen bond with a covalent bond. The hydrogen bond surrogate-based (HBS) α-helices contain a carbon-carbon bond derived from a ring-closing metathesis reaction. (b) Crystal structure of the HBS α-helix with electron density map superimposed onto the refined molecular model. (c) Putative i and i+4 hydrogen bonds (magenta lines) in crystal structure-derived molecular model of HBS helix. (d) Overlay of crystal structure and a model of an idealized α-helix.
Figure 3
Figure 3
Miniature proteins that display stable helical folds: (a) avian pancreatic protein (PDB code: 1ppt), (b) Trp cage (PDB code: 1l2y), (c) zinc finger protein (PDB code: 1a1l), and (d) Z domain of stapphylococcal protein A (PDB code: 2b88).
See this image and copyright information in PMC

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