Application of encoded library technology (ELT) to a protein-protein interaction target: Discovery of a potent class of integrin lymphocyte function-associated antigen 1 (LFA-1) antagonists

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• 作者：Christopher S. Kollmann^a ; Xiaopeng Bai^a ; Ching-Hsuan Tsai^a ; Hongfang Yang^a ; Kenneth E. Lind^a ; Steven R. Skinner^a ; Zhengrong Zhu^a ; David I. Israel^a ; John W. Cuozzo^a ; ^&dagger ; ; Barry A. Morgan^a ; Koichi Yuki^b ; ^&Dagger ; ; Can Xie^b ; ^§ ; ; Timothy A. Springer^b ; Motomu Shimaoka^b ; ^¶ ; ; Ghotas Evindar^a ; ^{ghotas.x.evindar@gsk.com" class="auth_mail}
• 关键词：ELT ; encoded library technology ; LFA-1 ; lymphocyte function-associated antigen 1 ; ICAM-1 ; intercellular adhesion molecule 1 ; PPI ; protein&ndash ; protein interactions
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：1 April, 2014
• 年：2014
• 卷：22
• 期：7
• 页码：2353-2365
• 全文大小：3310 K

文摘

The inhibition of protein-protein interactions remains a challenge for traditional small molecule drug discovery. Here we describe the use of DNA-encoded library technology for the discovery of small molecules that are potent inhibitors of the interaction between lymphocyte function-associated antigen 1 and its ligand intercellular adhesion molecule 1. A DNA-encoded library with a potential complexity of 4.1 billion compounds was exposed to the I-domain of the target protein and the bound ligands were affinity selected, yielding an enriched small-molecule hit family. Compounds representing this family were synthesized without their DNA encoding moiety and found to inhibit the lymphocyte function-associated antigen 1/intercellular adhesion molecule-1 interaction with submicromolar potency in both ELISA and cell adhesion assays. Re-synthesized compounds conjugated to DNA or a fluorophore were demonstrated to bind to cells expressing the target protein.