Diversity-oriented synthesis encoded by deoxyoligonucleotides.
Diversity-oriented synthesis encoded by deoxyoligonucleotides.
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DOI：
10.1038/s41467-023-40575-5
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发表时间：
2023-08-15
影响因子：
16.6
通讯作者：
Briner K
中科院分区：
文献类型：
--
作者：
Hudson L;Mason JW;Westphal MV;Richter MJR;Thielman JR;Hua BK;Gerry CJ;Xia G;Osswald HL;Knapp JM;Tan ZY;Kokkonda P;Tresco BIC;Liu S;Reidenbach AG;Lim KS;Poirier J;Capece J;Bonazzi S;Gampe CM;Smith NJ;Bradner JE;Coley CW;Clemons PA;Melillo B;Hon CS;Ottl J;Dumelin CE;Schaefer JV;Faust AME;Berst F;Schreiber SL;Zécri FJ;Briner K
面向多样性的合成（DOS）是一种强大的策略，可以制备商业筛选集合中具有代表性不足的特征的分子，从而阐明新的生物学机制。与 DOS 的发展同时，DNA 编码文库 (DEL) 已成为一种有效、高效的筛选策略，用于识别蛋白质结合物。尽管该领域最近取得了进展，但大多数 DEL 合成仍受到敏感 DNA 构建体的限制。在这里，我们描述了对 370 万成员 DEL 进行的设计、合成和验证实验，这些实验使用具有不同退出向量的不同骨架架构生成并源自 DOS，以实现超出仅通过改变附属物所能实现的结构多样性。我们还展示了三种不同蛋白质靶标的筛选结果。我们将向学术科学界提供此 DEL，以增加对新颖结构特征的获取并加速早期药物发现。大多数 DNA 编码文库 (DEL) 合成都受到敏感 DNA 构建体的限制。在此，作者开发了 DOSEDO，这是一种 370 万种多样化的化合物 DEL，通过面向多样性的合成生成，可提供增强的支架和退出载体多样性，并为多个蛋白质靶点提供经过验证的结合命中。
Diversity-oriented synthesis (DOS) is a powerful strategy to prepare molecules with underrepresented features in commercial screening collections, resulting in the elucidation of novel biological mechanisms. In parallel to the development of DOS, DNA-encoded libraries (DELs) have emerged as an effective, efficient screening strategy to identify protein binders. Despite recent advancements in this field, most DEL syntheses are limited by the presence of sensitive DNA-based constructs. Here, we describe the design, synthesis, and validation experiments performed for a 3.7 million-member DEL, generated using diverse skeleton architectures with varying exit vectors and derived from DOS, to achieve structural diversity beyond what is possible by varying appendages alone. We also show screening results for three diverse protein targets. We will make this DEL available to the academic scientific community to increase access to novel structural features and accelerate early-phase drug discovery. Most DNA-encoded library (DEL) syntheses are limited by the presence of sensitive DNA-based constructs. Here, the authors develop DOSEDO, a diverse 3.7 million compound DEL, generated through diversity-oriented synthesis that provides enhanced scaffold and exit vector diversity and gives validated binding hits for multiple protein targets.
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影响因子：
9.8
作者：
Halpin DR;Lee JA;Wrenn SJ;Harbury PB
通讯作者：
Harbury PB
影响因子：
64.8
作者：
Kato N;Comer E;Sakata-Kato T;Sharma A;Sharma M;Maetani M;Bastien J;Brancucci NM;Bittker JA;Corey V;Clarke D;Derbyshire ER;Dornan GL;Duffy S;Eckley S;Itoe MA;Koolen KM;Lewis TA;Lui PS;Lukens AK;Lund E;March S;Meibalan E;Meier BC;McPhail JA;Mitasev B;Moss EL;Sayes M;Van Gessel Y;Wawer MJ;Yoshinaga T;Zeeman AM;Avery VM;Bhatia SN;Burke JE;Catteruccia F;Clardy JC;Clemons PA;Dechering KJ;Duvall JR;Foley MA;Gusovsky F;Kocken CH;Marti M;Morningstar ML;Munoz B;Neafsey DE;Sharma A;Winzeler EA;Wirth DF;Scherer CA;Schreiber SL
通讯作者：
Schreiber SL
影响因子：
4.2
作者：
Deng, Hongfeng;Zhou, Jingye;Zhou, Quan
通讯作者：
Zhou, Quan
影响因子：
--
作者：
Gerard, Baudouin;Duvall, Jeremy R.;Marcaurelle, Lisa A.
通讯作者：
Marcaurelle, Lisa A.
DOI：
10.1007/978-94-007-7359-2_11
发表时间：
2014-01-01
期刊：
CARBONIC ANHYDRASE: MECHANISM, REGULATION, LINKS TO DISEASE, AND INDUSTRIAL APPLICATIONS
影响因子：
--
作者：
Benej, Martin;Pastorekova, Silvia;Pastorek, Jaromir
通讯作者：
Pastorek, Jaromir