Truncation, randomization, and selection: generation of a reduced length c-Jun antagonist that retains high interaction stability.
Truncation, randomization, and selection: generation of a reduced length c-Jun antagonist that retains high interaction stability.
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DOI：
10.1074/jbc.m111.221267
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发表时间：
2011-08-26
期刊：
影响因子：
--
通讯作者：
Mason JM
中科院分区：
文献类型：
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作者：
Crooks RO;Rao T;Mason JM
转录调节因子激活蛋白-1的DNA结合活性显示出作为癌症治疗靶点的相当大的希望。已经采用了许多不同的策略来抑制这种蛋白质的功能，并在体外和体内都证明了这一点。基于肽的治疗剂在过去几年中重新受到关注，并且已经衍生出许多能够与Jun和Fos的卷曲螺旋二聚化结构域结合的37个氨基酸的肽。在这里，我们展示了如何截断和半理性库设计，然后通过蛋白质片段互补，可以用来产生亮氨酸拉链结合肽的迭代手段。为此，我们对FosW肽实施了这种策略以产生4 hFosW。该肽被截短了四个残基，具有非常有利的结合特性，并证明了设计逐渐更短的肽作为亮氨酸拉链拮抗剂同时保留亲本肽的许多关键特征的可能性。从可药用性和有效性的角度来看，是否需要低分子量拮抗剂还存在争议。然而，从合成成本以及确定结合所需的最小功能单元的角度来看，长度减少的拮抗剂值得细读。
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.