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PNA-Based Dynamic Combinatorial Libraries (PDCL) and screening of lectins.
Bioorganic & Medicinal Chemistry ( IF 3.5 ) Pub Date : 2020-03-26 , DOI: 10.1016/j.bmc.2020.115458
Lluc Farrera-Soler 1 , Jean-Pierre Daguer 1 , Patrick Raunft 1 , Sofia Barluenga 1 , Anne Imberty 2 , Nicolas Winssinger 1
Affiliation  

Selections from dynamic combinatorial libraries (DCL) benefit from the dynamic nature of the library that can change constitution upon addition of a selection pressure, such as ligands binding to a protein. This technology has been predominantly used with small molecules interacting with each other through reversible covalent interaction. However, application of this technology in biomedical research and drug discovery has been limited by the reversibility of covalent exchange and the analytical deconvolution of small molecule fragments. Here we report a supramolecular approach based on the use of a constant short PNA tag to direct the combinatorial pairing of fragment. This PNA tag yields fast exchange kinetics, while still delivering the benefits of cooperativity, and provides favourable properties for analytical deconvolution by MALDI. A selection from >6,000 assemblies of glycans (mono-, di-, tri-saccharides) targeting AFL, a lectin from pathogenic fungus, yielded a 95 nM assembly, nearly three orders of magnitude better in affinity than the corresponding glycan alone (41 µM).

中文翻译:

基于PNA的动态组合库(PDCL)和凝集素筛选。

从动态组合文库(DCL)中进行的选择受益于该文库的动态性质,该性质可以在添加选择压力(例如与蛋白质结合的配体)时改变结构。该技术已主要用于通过可逆共价相互作用彼此相互作用的小分子。但是,该技术在生物医学研究和药物发现中的应用受到共价交换的可逆性和小分子片段的分析去卷积的限制。在这里,我们报告了基于使用恒定的短PNA标签指导片段的组合配对的超分子方法。这种PNA标签可产生快速的交换动力学,同时仍具有协同作用的优点,并为MALDI进行分析反卷积提供了有利的特性。
更新日期:2020-04-20
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