期刊
FASEB JOURNAL
卷 24, 期 7, 页码 2201-2210出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.09-143008
关键词
Bcl-2 family; BH3 domain; therapeutic peptide
资金
- Japan Ministry of Education, Culture, Sports, Science, and Technology (MEXT)
- New Energy and Industrial Technology Development Organization (NEDO) of Japan
Bcl-X-L, 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-X-L 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 mu M) than Bak BH3 (IC50 = 11.8 mu M) for Bcl-X-L in vitro. We also found that GFP fusions of the selected peptides specifically interact with Bcl-X-L, 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-X-L and overcomes the effects of Bcl-X-L 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.-Matsumura, N., Tsuji, T., Sumida, T., Kokubo, M., Onimaru, M., Doi, N., Takashima, H., Miyamoto-Sato, E., Yanagawa, H. mRNA display selection of a high-affinity, Bcl-X-L-specific binding peptide. FASEB J. 24, 2201-2210 (2010). www.fasebj.org
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