Potent alpha 4 beta 1 peptide antagonists as potential anti-inflammatory agents.

Abstract

The migration, adhesion, and subsequent extravasation of leukocytes into inflamed tissues contribute to the pathogenesis of a variety of inflammatory diseases including asthma, rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. The integrin adhesion receptor alpha 4 beta 1 expressed on leukocytes binds to the extracellular matrix protein fibronectin and to the cytokine inducible vascular cell adhesion molecule-1 (VCAM-1) at inflamed sites. Binding of alpha 4 beta 1 to VCAM-1 initiates firm adhesion of the leukocyte to the vascular endothelium followed by extravasation into the tissue. Monoclonal antibodies generated against either alpha 4 beta 1 or VCAM-1 can moderate this inflammatory response in a variety of animal models. Recently peptides containing a consensus LDV sequence based on the connecting segment-1 (CS-1) of fibronectin and cyclic peptides containing an RCD motif have shown promise in modulating leukocyte migration and inflammation presumably by blocking the interaction of alpha 4 beta 1 with VCAM-1. Here we describe novel, highly potent, cyclic peptides that competitively inhibit alpha 4 beta 1 binding to VCAM-1 and fibronectin at sub nanomolar concentrations. The structure of a representative analog was determined via NMR spectroscopy and used to facilitate optimization of peptide leads. The peptides discussed here utilize similar functional groups as the binding epitope of VCAM-1, inhibit lymphocyte migration in vivo, and are highly selective for alpha 4 beta 1. Furthermore the structure--activity relationships described here have provided a template for the structure-based design of small molecule antagonists of alpha 4 beta 1-mediated cell adhesion processes.

• Authors: D Y Jackson, C Quan, D R Artis, T Rawson, B Blackburn, M Struble, G Fitzgerald, K Chan, S Mullins, J P Burnier, W J Fairbrother, K Clark, M Berisini, H Chui, M Renz, S Jones, S Fong
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 40 Issue 21 Pg. 3359-68 (Oct 10 1997) ISSN: 0022-2623 [Print] United States
• PMID: 9341911 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Antibodies, Monoclonal
• Integrin alpha4beta1
• Integrins
• Peptides, Cyclic
• Receptors, Lymphocyte Homing
• Vascular Cell Adhesion Molecule-1

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (chemical synthesis, chemistry, metabolism, pharmacology)
• Antibodies, Monoclonal (immunology)
• Binding, Competitive
• Cell Adhesion (drug effects)
• Cell Movement (drug effects)
• Integrin alpha4beta1
• Integrins (antagonists & inhibitors, immunology, metabolism)
• Lymphocytes (drug effects, physiology)
• Magnetic Resonance Spectroscopy
• Mass Spectrometry
• Mice
• Models, Molecular
• Molecular Structure
• Peptides, Cyclic (chemical synthesis, chemistry, metabolism, pharmacology)
• Receptors, Lymphocyte Homing (antagonists & inhibitors, immunology, metabolism)
• Structure-Activity Relationship
• Vascular Cell Adhesion Molecule-1 (chemistry, immunology, metabolism)