title: 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.affiliation: Department of Bioorganic Chemistry, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: D Y
authors.initials: DY
authors.lastname: Jackson
authors.forename: C
authors.initials: C
authors.lastname: Quan
authors.forename: D R
authors.initials: DR
authors.lastname: Artis
authors.forename: T
authors.initials: T
authors.lastname: Rawson
authors.forename: B
authors.initials: B
authors.lastname: Blackburn
authors.forename: M
authors.initials: M
authors.lastname: Struble
authors.forename: G
authors.initials: G
authors.lastname: Fitzgerald
authors.forename: K
authors.initials: K
authors.lastname: Chan
authors.forename: S
authors.initials: S
authors.lastname: Mullins
authors.forename: J P
authors.initials: JP
authors.lastname: Burnier
authors.forename: W J
authors.initials: WJ
authors.lastname: Fairbrother
authors.forename: K
authors.initials: K
authors.lastname: Clark
authors.forename: M
authors.initials: M
authors.lastname: Berisini
authors.forename: H
authors.initials: H
authors.lastname: Chui
authors.forename: M
authors.initials: M
authors.lastname: Renz
authors.forename: S
authors.initials: S
authors.lastname: Jones
authors.forename: S
authors.initials: S
authors.lastname: Fong
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000276:immunology; D001667:Binding, Competitive; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D039041:Integrin alpha4beta1; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects / Q000502:physiology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D016201:Receptors, Lymphocyte Homing / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D013329:Structure-Activity Relationship; D019010:Vascular Cell Adhesion Molecule-1 / Q000737:chemistry / Q000276:immunology / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D039041:Integrin alpha4beta1; D016023:Integrins; D010456:Peptides, Cyclic; D016201:Receptors, Lymphocyte Homing; D019010:Vascular Cell Adhesion Molecule-1