mRNA display selection of a high-affinity, Bcl-XL-specific binding peptide

Nobutaka Matsumura, Toru Tsuji, Takeshi Sumida, Masahito Kokubo, Michiko Onimaru, Nobuhide Doi, Hideaki Takashima, Etsuko Miyamoto-Sato, Hiroshi Yanagawa

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Bcl-XL, an antiapoptotic member of the Bcl-2 family, is a mitochondrial protein that inhibits activation of Bax and Bak, which commit the cell to apoptosis, and it therefore represents a potential target for drug discovery. Peptides have potential as therapeutic molecules because they can be designed to engage a larger portion of the target protein with higher specificity. In the present study, we selected 16-mer peptides that interact with Bcl-XL from random and degenerate peptide libraries using mRNA display. The selected peptides have sequence similarity with the Bcl-2 family BH3 domains, and one of them has higher affinity (IC50=0.9 μM) than Bak BH3 (IC50=11.8 μM) for Bcl-XL in vitro. We also found that GFP fusions of the selected peptides specifically interact with Bcl-XL, localize in mitochondria, and induce cell death. Further, a chimeric molecule, in which the BH3 domain of Bak protein was replaced with a selected peptide, retained the ability to bind specifically to Bcl-X L. These results demonstrate that this selected peptide specifically antagonizes the function of Bcl-XL and overcomes the effects of Bcl-XL in intact cells. We suggest that mRNA display is a powerful technique to identify peptide inhibitors with high affinity and specificity for disease-related proteins.

Original languageEnglish
Pages (from-to)2201-2210
Number of pages10
JournalFASEB Journal
Volume24
Issue number7
DOIs
Publication statusPublished - 2010 Jul 1

Keywords

  • BH3 domain
  • Bcl-2 family
  • Therapeutic peptide

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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    Matsumura, N., Tsuji, T., Sumida, T., Kokubo, M., Onimaru, M., Doi, N., Takashima, H., Miyamoto-Sato, E., & Yanagawa, H. (2010). mRNA display selection of a high-affinity, Bcl-XL-specific binding peptide. FASEB Journal, 24(7), 2201-2210. https://doi.org/10.1096/fj.09-143008