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- Title
mRNA display selection of a high-affinity, Bcl-X<sub>L</sub>-specific binding peptide.
- Authors
Matsumura, Nobutaka; Tsuji, Toru; Sumida, Takeshi; Kokubo, Masahito; Onimaru, Michiko; Doi, Nobuhide; Takashima, Hideaki; Miyamoto-Sato, Etsuko; Yanagawa, Hiroshi
- 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-XL. 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.
- Subjects
CELL death; APOPTOSIS prevention; MITOCHONDRIAL DNA; PROTEINS; MESSENGER RNA; PEPTIDES; PREVENTION
- Publication
FASEB Journal, 2010, Vol 24, Issue 7, p2201
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.09-143008