Novel cyclic and linear oligopeptides that bind to integrin beta1 chain and either inhibit or costimulate T lymphocytes.
There is a redundancy of cellular beta1 integrin (very late antigen or VLA) receptors that mediate interactions between different extracellular matrix proteins (ECMP) and T lymphocytes. This suggests that antagonists targeted at individual VLA receptors may be of limited therapeutic efficacy in T cell-mediated diseases and that agents such as monoclonal antibody 4B4, which bind to the common integrin beta1 chain and inhibit interactions between effector T cells and a range of ECMP, may be of greater therapeutic interest if toxicity can be avoided. We have therefore sought proof of principle as to whether small molecules that interact with the integrin beta1 chain at or near the 4B4 binding site can modulate T cell costimulation and adhesion in the presence of type I collagen or fibronectin (FN). Two phage display libraries, each expressing more than 10(9) independent cyclic or linear 7-mer peptides, were used to identify molecules of interest by an enrichment process involving specific recovery of phage bound to a human T cell line by elution with a large excess of 4B4 antibody. Novel cyclic and linear peptides have thus been identified and found to inhibit interactions between T cells and both type I collagen and fibronectin. A separate cyclic peptide was found to costimulate T cells in a beta1 integrin-dependent manner. These findings form a basis for the development of small molecules that interact in inhibitory or stimulatory capacities with the common integrin beta1 chain, and may be of interest as therapeutic antagonists or immunologic adjuvants.
Rao
Wei Hong
WH
Division of Dermatology, University of Leicester, Medical Sciences Building, University Road, Leicester LE1 9HN, UK.
Camp
Richard D R
RD
D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D003001:Cloning, Molecular; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006801:Humans; D007202:Indicators and Reagents; D019012:Integrin beta1 / Q000378:metabolism*; D009842:Oligopeptides / Q000378:metabolism* / Q000494:pharmacology*; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D013601:T-Lymphocytes / Q000187:drug effects*
D016326:Extracellular Matrix Proteins; D007202:Indicators and Reagents; D019012:Integrin beta1; D009842:Oligopeptides; D019151:Peptide Library; D010456:Peptides, Cyclic