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Biological Chemistry

Cross-Linking Technique Could Complement Peptide Stapling

Method stabilizes proteins without the need for metal catalysts or nonnatural amino acids

by Carmen Drahl
April 29, 2013 | A version of this story appeared in Volume 91, Issue 17

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Credit: Adapted from J. Am. Chem. Soc.
A new stapling technique uses hexafluorobenzene to link two segments of this peptide.
A ribbon structure reaction scheme. On the left, one helix has two sulfide groups hanging off. On the right, the sulfide groups have both bound to the same fluorinated benzene ring.
Credit: Adapted from J. Am. Chem. Soc.
A new stapling technique uses hexafluorobenzene to link two segments of this peptide.

When chemists say they’re stapling a peptide, what they’re actually doing is cross-linking some of the amino acid side chains to make the peptide more stable or to adjust its properties. MIT’s Bradley L. Pentelute, Tufts University’s Yu-Shan Lin, and coworkers have developed a new stapling technique that could complement established methods (J. Am. Chem. Soc., DOI: 10.1021/ja400119t). The researchers originally planned to develop a mild way to arylate a cysteine thiol, and they were adapting a known reaction between thiols and hexafluorobenzene for that purpose. But two cysteines consistently added to the benzene species instead of one, so they decided to focus on cross-linking instead. Stapling traditionally calls for nonnatural amino acids and a metal catalyst, but the new technique doesn’t require them. It is compatible with protein synthesis techniques, as the team demonstrated by building a stabilized three-helix protein that binds to a breast cancer biomarker.

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