Bicyclic peptide ligands pulled out of cysteine-rich peptide libraries

Shiyu Chen, Inmaculada Rentero Rebollo, Sergey A. Buth, Julia Morales-Sanfrutos, Jeremy Touati, Petr G. Leiman, Christian Heinis

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

Bicyclic peptide ligands were found to have good binding affinity and target specificity. However, the method applied to generate bicyclic ligands based on phage-peptide alkylation is technically complex and limits its application to specialized laboratories. Herein, we report a method that involves a simpler and more robust procedure that additionally allows screening of structurally more diverse bicyclic peptide libraries. In brief, phage-encoded combinatorial peptide libraries of the format XmCX nCXoCXp are oxidized to connect two pairs of cysteines (C). This allows the generation of 3 × (m + n + o + p) different peptide topologies because the fourth cysteine can appear in any of the (m + n + o + p) randomized amino acid positions (X). Panning of such libraries enriched strongly peptides with four cysteines and yielded tight binders to protein targets. X-ray structure analysis revealed an important structural role of the disulfide bridges. In summary, the presented approach offers facile access to bicyclic peptide ligands with good binding affinities.

Original languageEnglish (US)
Pages (from-to)6562-6569
Number of pages8
JournalJournal of the American Chemical Society
Volume135
Issue number17
DOIs
StatePublished - May 1 2013

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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    Chen, S., Rentero Rebollo, I., Buth, S. A., Morales-Sanfrutos, J., Touati, J., Leiman, P. G., & Heinis, C. (2013). Bicyclic peptide ligands pulled out of cysteine-rich peptide libraries. Journal of the American Chemical Society, 135(17), 6562-6569. https://doi.org/10.1021/ja400461h