Diaryl ureaLDV peptidomimetics as α4β1 integrin antagonists: synthesis, adhesion inhibition and toxicity evaluation on CCRF-CEM cell line

Abstract

The α₄β₁ (VLA-4) integrin plays an important role in the leukocytes migration to sites of inflammation and has been validated as a therapeutic target for treating inflammatory diseases. Two families of regioisomeric peptidomimetics based on the Leu-Asp-Val (LDV) motif recognized by the α₄β₁ integrin were synthesized. Their activity was evaluated through cell adhesion and cell detachment assays using the CCRF-CEM cell line (Human T cells lymphoblast-like). Among the 20 antagonists tested, 17 appeared to be a good inhibitor of the adhesion of CCRF-CEM to fibronectin with an IC₅₀ value of 24 μM, comparable to the reference LDV peptide derivative 2. The toxicity of the peptidomimetics was also controlled.