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

作者：Kollmann Christopher S; Bai Xiaopeng; Tsai Ching Hsuan; Yang Hongfang; Lind Kenneth E; Skinner Steven R; Zhu Zhengrong; Israel David I; Cuozzo John W; Morgan Barry A; Yuki Koichi; Xie Can; Springer Timothy A; Shimaoka Motomu; Evindar Ghotas^*

来源：Bioorganic & Medicinal Chemistry, 2014, 22(7): 2353-2365.

DOI：10.1016/j.bmc.2014.01.050

• Encoded Library Technology
• DNA-encoded libraries
• Affinity-based selections
• Lymphocyte Function-associated Antigen 1
• Intercellular Adhesion Molecule 1
• Protein-Protein Interactions

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.

• 出版日期2014-4-1