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June 2, 2008
Volume 86, Number 22
p. 20

Peptide Stabilization

There's More Than One Way To Steady A Helix

Carmen Drahl

Hydrocarbon stapling preorganizes flexible peptides into α-helical structures. The technique is based on linking peptide side chains together and builds on many other discoveries. Stapling has benefited from the versatile olefin metathesis reaction and from decades of research on stabilizing helices. In terms of technology, "We are where we are today because lots of laboratories have put considerable effort into understanding how to preorganize peptides into defined structures," says Jeffery W. Kelly, a protein-folding expert at Scripps Research Institute.

Many Options Selected strategies for making stable α-helical structures include (clockwise from top left) aromatic ring scaffolds, side-chain cross-links (red), β-peptide scaffolds, and replacing a hydrogen bond with a carbon–carbon bond.

Many strategies for preorganizing peptide chains into stable helices resemble stapling. Like that technique, they are based on linking peptide side chains together. Some of the braces are based on linkages commonly found in biology, such as amide bond connections between carboxylic acid- and amine-containing side chains. Others are made from disulfide linkages between side chains, which stabilize the three-dimensional structure of peptides such as insulin.

Because both of these bonds might easily degrade in a biological setting, researchers also looked beyond biology for stabilization inspiration. For instance, Robert H. Grubbs of California Institute of Technology and Gregory L. Verdine of Harvard University independently explored olefin metathesis technology for helix stabilization (Angew. Chem. Int. Ed. 1998, 37, 3281; J. Am. Chem. Soc. 2000, 122, 5891). The Verdine group's earliest work carefully examined how changing the length and position in space of the olefin-containing side chain affected helix stability. They found that the staple's location matters, with some staples actually making the helix less stable than before stapling.

Stapling technology also benefited from advance knowledge about how to position staples on a peptide chain. An α-helix, by definition, takes 3.4 amino acid residues to make one full turn. Helix stabilization experts had previously reached the consensus that the best results come from linking pairs of amino acids separated by three or six intervening residues. That way, the link will span one or two turns on the α-helix, respectively, placing the tethered side chains on the same side of the helix.

There are other ways to stabilize α-helices besides covalent side-chain linking. Some helix restraints are noncovalent, such as salt bridges formed between positively and negatively charged side chains, or metal-binding interactions. Different backbones, such as those made from short polymers of β-amino acids or chains of aromatic rings, can approximate the way amino acid side chains jut out in three dimensions from α-helical scaffolds. Other researchers have replaced one key hydrogen bond that appears within an α-helix' peptide backbone with a carbon–carbon bond, a chemical bracket that coaxes short peptides to coil into a helical shape.

These particular types of helix mimics have not advanced into preclinical development, but researchers have shown that they bind to their intended partners and can have antiviral or antibacterial activity in laboratory tests.

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Chemical & Engineering News
ISSN 0009-2347
Copyright © 2011 American Chemical Society

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