2. Academic Validation
  3. Synthesis and assay of retro-α4β1 integrin-targeting motifs

Synthesis and assay of retro-α4β1 integrin-targeting motifs

  • Eur J Med Chem. 2014 Feb 12:73:225-32. doi: 10.1016/j.ejmech.2013.12.009.
Samantha D Dattoli 1,  Rossella De Marco 2,  Monica Baiula 1,  Santi Spampinato 3,  Arianna Greco 4,  Alessandra Tolomelli 4,  Luca Gentilucci 5
Affiliations

Affiliations

  • 1 Dept. of Pharmacy and BioTechnology, University of Bologna, via Irnerio 48, 40126 Bologna, Italy.
  • 2 Dept. of Chemistry "G. Ciamician", University of Bologna, via Selmi 2, 40126 Bologna, Italy. Electronic address: rossella.demarco2@unibo.it.
  • 3 Dept. of Pharmacy and BioTechnology, University of Bologna, via Irnerio 48, 40126 Bologna, Italy. Electronic address: santi.spampinato@unibo.it.
  • 4 Dept. of Chemistry "G. Ciamician", University of Bologna, via Selmi 2, 40126 Bologna, Italy.
  • 5 Dept. of Chemistry "G. Ciamician", University of Bologna, via Selmi 2, 40126 Bologna, Italy. Electronic address: luca.gentilucci@unibo.it.
PMID: 24412498 DOI: 10.1016/j.ejmech.2013.12.009
Abstract

In recent years, several research groups proposed new peptidomimetic antagonists of integrins αvβ3, α5β1, αIIbβ3, αvβ6, αvβ5, etc. based on retro sequences of the classic integrin-binding motif RGD. The retro strategy is still largely ignored for the non-RGD-binding α4β1 Integrin. Herein we present the first examples of retro sequences for targeting this Integrin, composed of Asp or isoAsp equipped with an aromatic cap at the N-terminus, (S)-pyrrolidine-3-carboxylic acid (β(2)-Pro) as a constrained core, and the amino variant (AMPUMP) of the well-known α4-targeting diphenylurea MPUPA. We discuss α4β1 receptor affinity (SPA), cell adhesion assays, stability in mouse serum, and conformational analysis. For their significant ability to inhibit cell adhesion and remarkable stability, the retro-peptide mimetics BnCO-Asp-β-Pro-AMPUMP (3) and BnCO-isoAsp-β-Pro-AMPUMP (4) represent promising candidates for designing small molecules as potential anti-inflammatory agents.

Keywords

Cell adhesion inhibition; Diphenylurea; Isoaspartate; Peptidomimetics; Retro sequences; Scintillation proximity assay; VLA-4 ligands; β(2)-Proline.

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