Screening and optimization of phage display cyclic peptides against the WDR5 WBM site.
Screening and optimization of phage display cyclic peptides against the WDR5 WBM site.
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DOI：
10.1039/d3md00288h
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发表时间：
2023-10-18
影响因子：
4.1
通讯作者：
中科院分区：
文献类型：
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作者：
在众多的WD40家族蛋白中，WDR5是一种特别重要的多功能衔接蛋白，它可以与多种蛋白质复合物结合来调节基因的激活，因此被认为是抗癌药物开发中有希望的表观遗传靶点。尽管已经发现了许多抑制剂针对WDR 5中称为WIN位点的甘氨酸结合腔，但称为WBM位点的侧疏水腔受到的关注相当少。在此，我们的目标是获得具有高效力和选择性的新型WBM靶向肽抑制剂。我们采用了两种改进的生物淘选方法与二硫键约束的环肽噬菌体文库含有7个随机残基，并确定了几个肽与微摩尔结合活性的对接和结合试验。为了进一步优化稳定性和活性，在候选肽DH226027的环化中使用9个巯基反应性化学接头，其具有良好的结合亲和力。本研究为寻找靶向蛋白质相互作用的多肽提供了一种有效的方法，并为多肽模拟药物的研究开辟了更广阔的前景。我们报道了两种基于噬菌体展示技术的筛选方法，以筛选针对WDR 5 WBM位点的新型肽抑制剂，并获得了优化的环肽CYC 3，可对其进行进一步的生物学评价。
Of the various WD40 family proteins, WDR5 is a particularly important multifunctional adaptor protein that can bind to several protein complexes to regulate gene activation, so it was considered as a promising epigenetic target in anti-cancer drug development. Despite many inhibitors having been discovered directing against the arginine-binding cavity in WDR5 called the WIN site, the side hydrophobic cavity called the WBM site receives rather scant attention. Herein, we aim to obtain novel WBM-targeted peptidic inhibitors with high potency and selectivity. We employed two improved biopanning approaches with a disulfide-constrained cyclic peptide phage library containing 7 randomized residues and identified several peptides with micromole binding activity by docking and binding assay. To further optimize the stability and activity, 9 thiol-reactive chemical linkers were utilized in the cyclization of the candidate peptide DH226027, which had good binding affinity. This study provides an effective method to discover potent peptides targeting protein–protein interactions and highlights a broader perspective of peptide-mimic drugs. We reported two improved screenings based on the phage display technique to discover novel peptidic inhibitors against the WDR5 WBM site, and the optimized cyclic peptide CYC3 was acquired, which could be subjected to further biological evaluation.
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与WDR5的相互作用促进了MYC促进靶基因识别和肿瘤发生。
影响因子：
16
作者：
Thomas, Lance R.;Wang, Qingguo;Grieb, Brian C.;Phan, Jason;Foshage, Audra M.;Sun, Qi;Olejniczak, Edward T.;Clark, Travis;Dey, Soumyadeep;Lorey, Shelly;Alicie, Bethany;Howard, Gregory C.;Cawthon, Bryan;Ess, Kevin C.;Eischen, Christine M.;Zhao, Zhongming;Fesik, Stephen W.;Tansey, William P.
通讯作者：
Tansey, William P.
影响因子：
--
作者：
Huang J;Ru B;Li S;Lin H;Guo FB
通讯作者：
Guo FB
影响因子：
7.3
作者：
Ho, Terence C. S.;Chan, Alex H. Y.;Ganesan, A.
通讯作者：
Ganesan, A.
影响因子：
7.3
作者：
Mudd, Gemma E.;Brown, Amy;Bennett, Gavin S.
通讯作者：
Bennett, Gavin S.
DOI：
10.1002/anie.201502607
发表时间：
2015-07-20
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
--
作者：
Assem N;Ferreira DJ;Wolan DW;Dawson PE
通讯作者：
Dawson PE