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

Bioorg Med Chem. 2014 Apr 1;22(7):2353-65. doi: 10.1016/j.bmc.2014.01.050. Epub 2014 Feb 7.

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.

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

MeSH terms

  • Cell Adhesion / drug effects
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Jurkat Cells
  • Ligands
  • Lymphocyte Function-Associated Antigen-1 / metabolism*
  • Molecular Structure
  • Protein Binding / drug effects
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship

Substances

  • Ligands
  • Lymphocyte Function-Associated Antigen-1
  • Small Molecule Libraries