Coupling Computational and Intracellular Screening and Selection Toward Co-compatible cJun and cFos Antagonists.,Biochemistry

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Coupling Computational and Intracellular Screening and Selection Toward Co-compatible cJun and cFos Antagonists.
Biochemistry ( IF 2.9 ) Pub Date : 2019-12-19 , DOI: 10.1021/acs.biochem.9b00631
Alexander Lathbridge ₁ , Anna S Michalowska ₁ , Jody M Mason ₁

Affiliation

Basic leucine-zipper (bZIP) proteins represent difficult, yet compelling, oncogenic targets since numerous cell-signaling cascades converge upon them, where they function to modulate the transcription of specific gene targets. bZIPs are widely recognized as important regulators of cellular processes that include cell proliferation, apoptosis, and differentiation. Once such validated transcriptional regulator, activator protein-1, is typically composed of heterodimers of Fos and Jun family members, with cFos-cJun being the best described. It has been shown to be key in the progression and development of a number of different diseases. As a proof-of-principle for our approach, we describe the first use of a novel combined in silico/in cellulo peptide-library screening platform that facilitates the derivation of a sequence that displays high selectivity for cJun relative to cFos, while also avoiding homodimerization. In particular, >60 million peptides were computationally screened and all potential on/off targets ranked according to predicted stability, leading to a reduced size library that was further refined by intracellular selection. The derived sequence is predicted to have limited cross-talk with a second previously derived peptide antagonist that is selective for cFos in the presence of cJun. The study provides new insight into the use of multistate screening with the ability to combine computational and intracellular approaches in evolving multiple cocompatible peptides that are capable of satisfying conflicting design requirements.

中文翻译：

将计算和细胞内筛选和选择结合起来以获得共相容的 cJun 和 cFos 拮抗剂。

碱性亮氨酸拉链 (bZIP) 蛋白代表了困难但引人注目的致癌靶标，因为许多细胞信号级联汇聚到它们上，它们的功能是调节特定基因靶标的转录。 bZIP 被广泛认为是细胞增殖、凋亡和分化等细胞过程的重要调节因子。经过验证的转录调节因子激活蛋白 1 通常由 Fos 和 Jun 家族成员的异二聚体组成，其中 cFos-cJun 是最好的描述。它已被证明是许多不同疾病的进展和发展的关键。作为我们方法的原理验证，我们描述了一种新颖的计算机/细胞内组合肽库筛选平台的首次使用，该平台有助于衍生出对 cJun 相对于 cFos 具有高选择性的序列，同时还避免了同二聚化。特别是，通过计算筛选了超过 6000 万种肽，并根据预测的稳定性对所有潜在的开启/关闭目标进行了排序，从而形成了尺寸减小的库，并通过细胞内选择进一步细化。预计衍生的序列与先前衍生的第二种肽拮抗剂的串扰有限，该肽拮抗剂在 cJun 存在的情况下对 cFos 具有选择性。该研究为多态筛选的使用提供了新的见解，能够将计算方法和细胞内方法结合起来，进化出能够满足相互冲突的设计要求的多种共相容肽。

更新日期：2019-12-19

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