Potent and specific peptide inhibitors of human pro-survival protein Bcl-xL.
Potent and specific peptide inhibitors of human pro-survival protein Bcl-xL.
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DOI：
10.1016/j.jmb.2014.09.030
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发表时间：
2015-03-27
影响因子：
5.6
通讯作者：
Keating, Amy E.
中科院分区：
文献类型：
--
作者：
Dutta, Sanjib;Ryan, Jeremy;Chen, T. Scott;Kougentakis, Christos;Letai, Anthony;Keating, Amy E.
Bcl-2蛋白家族在调节细胞凋亡中起着关键作用，并且促存活Bcl-2家族成员由于其在不同癌症中的过表达而成为重要的治疗靶标。促凋亡的BH 3-only蛋白通过直接结合到它们来拮抗促存活Bcl-2蛋白的功能，并且称为敏化剂的BH 3-only蛋白的亚类可以响应于不同的信号经由该机制启动凋亡。五种促存活蛋白Bcl-xL、Mcl-1、Bcl-2、Bcl-w和Bfl-1的结合偏好不同，其中Bcl-xL、Bcl-2和Bcl-w对许多天然敏化剂和小分子具有相似的相互作用谱。选择性结合仅一个或一个亚组家族成员的肽已显示出在诊断癌细胞中的凋亡阻断的测定中以及作为用于剖析凋亡机制的试剂的实用性。结合计算设计、组合文库筛选和合理诱变，我们设计了一系列BH 3敏化肽，其以亚纳摩尔的亲和力和选择性结合Bcl-xL，比四种竞争促存活蛋白中的每一种高1000倍。我们证明了我们设计的BH 3肽在区分依赖于不同促生存蛋白的癌细胞的测定中的功效。
The Bcl-2 family of proteins plays a critical role regulating apoptosis, and pro-survival Bcl-2 family members are important therapeutic targets due to their overexpression in different cancers. Pro-apoptotic BH3-only proteins antagonize pro-survival Bcl-2 protein functions by binding directly to them, and a sub-class of BH3-only proteins termed sensitizers can initiate apoptosis via this mechanism in response to diverse signals. The five pro-survival proteins Bcl-xL, Mcl-1, Bcl-2, Bcl-w and Bfl-1 differ in their binding preferences, with Bcl-xL, Bcl-2 and Bcl-w sharing similar interaction profiles for many natural sensitizers and small molecules. Peptides that bind selectively to just one or a subset of family members have shown utility in assays that diagnose apoptotic blockades in cancer cells and as reagents for dissecting apoptotic mechanism. Combining computational design, combinatorial library screening and rational mutagenesis, we designed a series of BH3 sensitizer peptides that bind Bcl-xL with sub-nanomolar affinity and selectivity up to 1000-fold over each of the four competing pro-survival proteins. We demonstrate the efficacy of our designed BH3 peptides in assays that differentiate between cancer cells that are dependent on different pro-survival proteins.
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影响因子：
64.5
作者：
Mason, Kylie D.;Carpinelli, Marina R.;Kile, Benjamin T.
通讯作者：
Kile, Benjamin T.
DOI：
10.1073/pnas.1303002110
发表时间：
2013-09-03
影响因子：
11.1
作者：
Chang, Yong S.;Graves, Bradford;Sawyer, Tomi K.
通讯作者：
Sawyer, Tomi K.
影响因子：
50.3
作者：
Certo, Michael;Moore, Victoria Del Gaizo;Letai, Anthony
通讯作者：
Letai, Anthony
影响因子：
4
作者：
Dutta, Sanjib;Chen, T. Scott;Keating, Amy E.
通讯作者：
Keating, Amy E.
影响因子：
5.6
作者：
Dutta S;Gullá S;Chen TS;Fire E;Grant RA;Keating AE
通讯作者：
Keating AE