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Inhibition of plasminogen activator inhibitor-1 binding to endocytosis receptors of the low density lipoprotein receptor family by a peptide isolated from a phage displayed library

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The functions of the serpin plasminogen activator inhibitor-1 (PAI-1) are based on molecular interactions with its target proteases urokinase-type and tissue-type plasminogen activator (uPA and tPA), with vitronectin, and with endocytosis receptors of the low density lipoprotein family. Understanding the significance of these interactions would be facilitated by the ability to block them individually. Using phage display, we have identified the disulphide constrained peptide motif CFGWC with affinity for natural human PAI-1. The three-dimensional structure of a peptide containing this motif (DVPCFGWCQDA) was determined by NMR. A binding site in the so-called flexible joint region of PAI-1 was suggested by molecular modelling and validated through binding studies with various competitors and site-directed mutagenesis of PAI-1. The peptide with an N-terminal biotin inhibited the binding of the uPA-PAI-1 complex to the endocytosis receptors low density lipoprotein receptor-related protein (LRP-1A) and very low density lipoprotein receptor (VLDLR) in vitro and inhibited endocytosis of the uPA-PAI-1 complex in U937 cells. We conclude that the isolated peptide represents a novel approach to pharmacological interference with the functions of PAI-1 based on inhibition of one specific molecular interaction.
Original languageEnglish
JournalBiochem. J.
Pages (from-to)387-396
Number of pages10
Publication statusPublished - 2006

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