Christopher S. Kollmann; Xiaopeng Bai; Ching-Hsuan Tsai; Hongfang Yang; Kenneth E. Lind; Steven R. Skinner; Zhengrong Zhu; David I. Israel; John W. Cuozzo; Barry A. Morgan; Koichi Yuki; Can Xie; Timothy A. Springer; Motomu Shimaoka; Ghotas Evindar
Bioorg. Med. Chem., 2014, 22, 7, 2353-2365
https://doi.org/10.1016/j.bmc.2014.01.050

Abstract

Abstract
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.
Graphical abstract
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.