PEPTIDE ANTAGONISTS TO TGF-BETA AS ANTITHROMBOTIC AGENTS

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DESCRIPTION: (Adapted from the Applicant's Abstract.) Plasminogen activator inhibitor-1 (PAI-1) has been implicated as a potential risk factor for myocardial infarction and as an inhibitor of pharmacological thrombolysis. Transforming growth factor-beta (TGF-beta), a major constituent of platelet lysates, induces PAI-1 release from vascular endothelial cells. The long term objective of the proposed research is to develop a peptide antagonist of TGF-beta and to validate its utility for adjunctive therapy to pharmacological thrombolysis and/or chronic therapy of patients with elevated levels of PAI-1. Specifically, the proposed studies will: 1) verify that rN10031, a peptide antagonist of TGF-beta, inhibits TGF-beta-induced PAI-1 release from vascular endothelial cells, and 2) identify structure/activity relationships critical to rN10031 which will allow optimization of its activity. rN10031, a 22 amino acid peptide, and analogues thereof will be tested for their ability to block PAI-1 release (measured immunochemically) from human vascular endothelial cells stimulated with varying concentrations of human platelet derived TGF-beta. Approximately 30 analogues will be prepared to identify residues of the rN10031 peptide critical for its antagonist activity. It is claimed that specific, potent TGF-beta antagonists offer the potential for development of a new class of drugs which regulate fibrinolysis.