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

• Published in: Bioorganic & medicinal chemistry Vol. 22; no. 7; pp. 2353 - 2365
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.04.2014; Elsevier
• Subjects: Affinity-based selections; Biochemistry & Molecular Biology; Cell Adhesion - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; DNA-encoded libraries; Dose-Response Relationship, Drug; Drug Discovery; Encoded Library Technology; Humans; Intercellular Adhesion Molecule 1; Jurkat Cells; Life Sciences & Biomedicine; Ligands; Lymphocyte Function-associated Antigen 1; Lymphocyte Function-Associated Antigen-1 - metabolism; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Protein Binding - drug effects; Protein-Protein Interactions; Science & Technology; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Structure-Activity Relationship; Affinity-based selections; Lymphocyte Function-associated Antigen 1; LFA-1; PPI; Encoded Library Technology; DNA-encoded libraries; ICAM-1; Intercellular Adhesion Molecule 1; ELT; Protein-Protein Interactions; SITE; DESIGN; MOLECULE; CHEMICAL LIBRARY; PEPTIDE; CONFORMATIONAL REGULATION; INHIBITORS; I-DOMAIN; BINDING; SUBUNIT
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2014.01.050

Encoded library technology (ELT) was utilized to identify a class of compounds that disrupt the interaction between lymphocyte function-associated antigen-1 (LFA-1) and its ligand intercellular adhesion molecule-1 (ICAM-1) at submicromolar potency in both ELISA and cell adhesion assays. 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.