Department of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, United Kingdom.
J Biol Chem. 2011 Aug 26;286(34):29470-9. doi: 10.1074/jbc.M111.221267. Epub 2011 Jun 22.
The DNA binding activity of the transcriptional regulator activator protein-1 shows considerable promise as a target in cancer therapy. A number of different strategies have been employed to inhibit the function of this protein with promise having been demonstrated both in vitro and in vivo. Peptide-based therapeutics have received renewed interest in the last few years, and a number of 37-amino acid peptides capable of binding to the coiled coil dimerization domain of Jun and Fos have been derived. Here, we demonstrate how truncation and semi-rational library design, followed by protein-fragment complementation, can be used to produce a leucine zipper binding peptide by iterative means. To this end, we have implemented this strategy on the FosW peptide to produce 4hFosW. This peptide is truncated by four residues with comparably favorable binding properties and demonstrates the possibility to design progressively shorter peptides to serve as leucine zipper antagonists while retaining many of the key features of the parent peptide. Whether or not the necessity for low molecular weight antagonists is required from the perspective of druggability and efficacy is subject to debate. However, antagonists of reduced length are worthy of perusal from the point of view of synthetic cost as well as identifying the smallest functional unit that is required for binding.
转录调控因子激活蛋白-1 的 DNA 结合活性有望成为癌症治疗的一个靶点。已经采用了许多不同的策略来抑制这种蛋白质的功能，无论是在体外还是在体内，都已经显示出了一定的效果。在过去几年中，基于肽的治疗方法重新受到关注，已经衍生出了许多能够与 Jun 和 Fos 的卷曲螺旋二聚化结构域结合的 37 个氨基酸肽。在这里，我们展示了如何通过截短和半理性文库设计，然后通过蛋白质片段互补，通过迭代方法产生一个亮氨酸拉链结合肽。为此，我们已经在 FosW 肽上实施了这种策略，生成了 4hFosW。该肽通过四个残基截断，具有类似的有利结合特性，并证明了设计越来越短的肽作为亮氨酸拉链拮抗剂的可能性，同时保留了亲本肽的许多关键特征。从可药性和疗效的角度来看，是否需要低分子量拮抗剂，这是有争议的。然而，从合成成本的角度来看，以及从识别所需的最小功能单元的角度来看，长度缩短的拮抗剂是值得研究的。
