结合不稳定FKBP12的Shield-1肽模拟物的设计与组合开发

IF 3.784 3区 化学 Q1 Chemistry
Daniel Madsen, Frederik P. Jørgensen, Daniel Palmer, Milena E. Roux, Jakob V. Olsen, Mikael Bols, Sanne Schoffelen, Frederik Diness*, Morten Meldal*
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引用次数: 3

摘要

在计算设计的基础上,在微粒子编码的PEGA1900微球上制备了一个聚焦的单头单化合物文库。该文库筛选了人类FKBP12蛋白的双点突变版本,称为不稳定结构域(DD)。受解码文库点击的启发,非天然肽结构在一种新的头上试验中进行筛选,这对于在头外再合成之前进行快速结构评估是有用的。随后,研究人员制备了19个化合物,并使用竞争性荧光偏振法进行了测试,结果发现了对DD具有低微摩尔结合亲和力的肽配体。该方法代表了一种快速鉴定新型结构支架的方法,其中筛选和初始结构优化是使用少量文库构建块完成的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Design and Combinatorial Development of Shield-1 Peptide Mimetics Binding to Destabilized FKBP12

Design and Combinatorial Development of Shield-1 Peptide Mimetics Binding to Destabilized FKBP12

On the basis of computational design, a focused one-bead one-compound library has been prepared on microparticle-encoded PEGA1900 beads consisting of small tripeptides with a triazole-capped N-terminal. The library was screened towards a double point-mutated version of the human FKBP12 protein, known as the destabilizing domain (DD). Inspired by the decoded library hits, unnatural peptide structures were screened in a novel on-bead assay, which was useful for a rapid structure evaluation prior to off-bead resynthesis. Subsequently, a series of 19 compounds were prepared and tested using a competitive fluorescence polarization assay, which led to the discovery of peptide ligands with low micromolar binding affinity towards the DD. The methodology represents a rapid approach for identification of a novel structure scaffold, where the screening and initial structure refinement was accomplished using small quantities of library building blocks.

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来源期刊
ACS Combinatorial Science
ACS Combinatorial Science CHEMISTRY, APPLIED-CHEMISTRY, MEDICINAL
自引率
0.00%
发文量
0
审稿时长
1 months
期刊介绍: The Journal of Combinatorial Chemistry has been relaunched as ACS Combinatorial Science under the leadership of new Editor-in-Chief M.G. Finn of The Scripps Research Institute. The journal features an expanded scope and will build upon the legacy of the Journal of Combinatorial Chemistry, a highly cited leader in the field.
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