Abstract
The Leu-Asp-Val-(LDV)-containing amino acid sequence, derived from the alternatively spliced first connecting segment region of fibronectin (FN), was shown to be recognized primarily by the alpha 4 beta 1-integrin receptor expressed on the surface of various cell types. This adhesion epitope may therefore inhibit integrin-mediated cell interactions with the extracellular matrix glycoprotein, including adhesion, migration, activation and differentiation. To probe the structural requirements for LDV recognition by integrins and examine the feasibility of inhibition of LDV-dependent cell-FN interactions, we have designed and constructed a novel psi-S-CH2 peptide bond surrogate that was employed in the formation of LDV surrogates. The synthesis of the psi-S-CH2 surrogates reported herein is based on Michael addition of 4-methylpentane thiol to an itaconic acid diester to form an S-CH2 bond. We have found that the LDV surrogates comprises of 4-methylpentanoate-Asp-i-butyl amide and 8-methyl-3-(2-methylpropylaminocarbonyl)-5-thianonanoic acid interfered with CD4+ human T-cell adhesion to FN in vitro, with an ED50 of 280 micrograms/mL. A control structural mimetic of the Leu-Glu-Val (LEV) peptide did not interfere with the T-cell-FN interaction. The specificity of the reaction was substantiated by the finding that the LDV mimetics did not interfere with T-cell adhesion to laminin, another major cell-adhesive glycoprotein of the extracellular matrix.(ABSTRACT TRUNCATED AT 250 WORDS)
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