Discovery of Small-Molecule Interleukin-2 Inhibitors from a DNA-Encoded Chemical Library

被引：80

作者：

Leimbacher, Markus ^{[1
]}

Zhang, Yixin ^{[1
]}

Mannocci, Luca ^{[2
]}

Stravs, Michael ^{[1
]}

Geppert, Tim ^{[1
]}

Scheuermann, Joerg ^{[1
]}

Schneider, Gisbert ^{[1
]}

Neri, Dario ^{[1
]}

机构：

[1] Inst Pharmaceut Sci, Dept Chem & Appl Biosci, CH-8093 Zurich, Switzerland

[2] Philochem AG, CH-8112 Otelfingen, Switzerland

来源：

CHEMISTRY-A EUROPEAN JOURNAL | 2012年 / 18卷 / 25期

基金：

瑞士国家科学基金会;

关键词：

DNA-encoded chemical libraries; drug discovery; high-throughput screening; inhibitors; ligands; DRUG DISCOVERY; CARBONIC-ANHYDRASES; ALPHA-RECEPTOR; CHEMISTRY; SELECTION; BINDING; DESIGN; IDENTIFICATION; MACROCYCLES; STRATEGY;

D O I：

10.1002/chem.201200952

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Libraries of chemical compounds individually coupled to encoding DNA tags (DNA-encoded chemical libraries) hold promise to facilitate exceptionally efficient ligand discovery. We constructed a high-quality DNA-encoded chemical library comprising 30?000 drug-like compounds; this was screened in 170 different affinity capture experiments. High-throughput sequencing allowed the evaluation of 120 million DNA codes for a systematic analysis of selection strategies and statistically robust identification of binding molecules. Selections performed against the tumor-associated antigen carbonic anhydrase IX (CA IX) and the pro-inflammatory cytokine interleukin-2 (IL-2) yielded potent inhibitors with exquisite target specificity. The binding mode of the revealed pharmacophore against IL-2 was confirmed by molecular docking. Our findings suggest that DNA-encoded chemical libraries allow the facile identification of drug-like ligands principally to any protein of choice, including molecules capable of disrupting high-affinity proteinprotein interactions.

引用

页码：7729 / 7737

页数：9

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