Stabilizing the Pro-Apoptotic BimBH3 Helix (BimSAHB) Does Not Necessarily Enhance Affinity or Biological Activity
Stabilizing the Pro-Apoptotic BimBH3 Helix (BimSAHB) Does Not Necessarily Enhance Affinity or Biological Activity
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DOI：
10.1021/cb3005403
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发表时间：
2013-02-01
影响因子：
4
通讯作者：
Czabotar, Peter E.
中科院分区：
文献类型：
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作者：
Okamoto, Toru;Zobel, Kerry;Czabotar, Peter E.
用于开发治疗肽的有吸引力的方法是通过稳定其α-螺旋构象来增强与其靶标的结合，例如，设计用于诱导细胞凋亡的稳定化的BimBH 3肽（BimSAHB）。出乎意料的是，我们发现这种修饰的肽对它们的靶点，即促生存Bcl-2蛋白的亲和力降低。我们将这种亲和力的丧失归因于天然肽结合态中存在的稳定分子内相互作用网络的破坏。改变这种网络可能会损害结合亲和力，如本文研究的BimBH 3钉合肽的情况。此外，暴露于这些肽的细胞不容易发生凋亡，强烈表明BimSAHB不是固有的细胞渗透性。
An attractive approach for developing therapeutic peptides is to enhance binding to their targets by stabilizing their a-helical conformation, for example, stabilized BimBH3 peptides (BimSAHB) designed to induce apoptosis. Unexpectedly, we found that such modified peptides have reduced affinity for their targets, the pro-survival Bcl-2 proteins. We attribute this loss in affinity to disruption of a network of stabilizing intramolecular interactions present in the bound state of the native peptide. Altering this network may compromise binding affinity, as in the case of the BimBH3 stapled peptide studied here. Moreover, cells exposed to these peptides do not readily undergo apoptosis, strongly indicating that BimSAHB is not inherently cell permeable.