Highly pure DNA-encoded chemical libraries by dual-linker solid-phase synthesis

被引：13

作者：

Keller, Michelle ^{[1
]}

Petrov, Dimitar ^{[1
]}

Gloger, Andreas ^{[1
]}

Dietschi, Bastien ^{[1
]}

Jobin, Kilian ^{[1
]}

Gradinger, Timon ^{[1
]}

Martinelli, Adriano ^{[2
]}

Plais, Louise ^{[1
]}

Onda, Yuichi ^{[1
]}

Neri, Dario ^{[1
,3
]}

Scheuermann, Joerg ^{[1
]}

机构：

[1] Swiss Fed Inst Technol, Dept Chem & Appl Biosci, CH-8093 Zurich, Switzerland

[2] Swiss Fed Inst Technol, Dept Biol, CH-8093 Zurich, Switzerland

[3] Philogen SpA, I-53100 Siena, Italy

来源：

SCIENCE | 2024年 / 384卷 / 6701期

基金：

瑞士国家科学基金会; 欧盟地平线“2020”;

关键词：

TEMPLATED ORGANIC-SYNTHESIS; PEPTIDE-SYNTHESIS; HUMAN-ANTIBODIES; SELECTION; DESIGN; IDENTIFICATION; INHIBITORS; DISCOVERY; LIGANDS; OPTIMIZATION;

D O I：

10.1126/science.adn3412

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The first drugs discovered using DNA-encoded chemical library (DEL) screens have entered late-stage clinical development. However, DEL technology as a whole still suffers from poor chemical purity resulting in suboptimal performance. In this work, we report a technique to overcome this issue through self-purifying release of the DEL after magnetic bead-based synthesis. Both the first and last building blocks of each assembled library member were linked to the beads by tethers that could be cleaved by mutually orthogonal chemistry. Sequential cleavage of the first and last tether, with washing in between, ensured that the final library comprises only the fully complete compounds. The outstanding purity attained by this approach enables a direct correlation of chemical display and encoding, allows for an increased chemical reaction scope, and facilitates the use of more diversity elements while achieving greatly improved signal-to-noise ratios in selections.

引用

页码：1259 / 1265

页数：7

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