Synthesis and Screening of a DNA-Encoded Library of Non-Peptidic Macrocycles.
Synthesis and Screening of a DNA-Encoded Library of Non-Peptidic Macrocycles.
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非肽大环的DNA编码库的合成和筛选。
DOI：
10.1002/anie.202116999
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发表时间：
2022-04-25
影响因子：
16.6
通讯作者：
Kodadek, Thomas
中科院分区：
文献类型：
--
作者：
Koesema, Eric;Roy, Animesh;Paciaroni, Nicholas G.;Coito, Carlos;Tokmina-Roszyk, Michal;Kodadek, Thomas
关键词：
非肽大环库作为难对付靶标配体的来源，受到了人们的极大关注。我们在这里报道了一个含有几十万个硫醚连接的大环的DNA编码库的固相合成。该文库的设计目的是在骨架支架多样性方面高度多样化，并将损害细胞渗透性的酰胺N−H键的数量降至最低。通过分离与链霉亲和素高亲和力结合的化合物，证明了该文库作为蛋白质配体来源的实用性。“不能用药的蛋白质组”的配基的发现可能需要开发新的化学物质，其“分子翼展”比传统的利平斯基顺应性小分子要大。构建了非肽硫醚大环DNA编码库，并筛选出与模型蛋白SA具有高亲和力的蛋白质配体。
There is considerable interest in the development of libraries of non‐peptidic macrocycles as a source of ligands for difficult targets. We report here the solid‐phase synthesis of a DNA‐encoded library of several hundred thousand thioether‐linked macrocycles. The library was designed to be highly diverse with respect to backbone scaffold diversity and to minimize the number of amide N−H bonds, which compromise cell permeability. The utility of the library as a source of protein ligands is demonstrated through the isolation of compounds that bind Streptavidin, a model target, with high affinity. The discovery of ligands for the “undruggable proteome” is likely to require the development of new chemical matter with a greater “molecular wingspan” than traditional Lipinski‐compliant small molecules. A DNA‐encoded library (DEL) of non‐peptidic thioether macrocycles has been constructed and screened for high affinity protein ligands to a model protein, SA.
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影响因子：
46.2
作者：
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通讯作者：
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Kihlberg, Jan
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