Plasminogen activator inhibitor-I (PAI-I) 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-I release from vascular endothelial cells. The long-term objective 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-I. Specifically, the studies will:(1) verify that rN 10031, a peptide antagonist of TGF-beta, inhibits TGF-beta-induced PAI-I release from vascular endothelial cells, and(2) identify structure/activity relationships critical to rN 10031 which will allow optimization of its activity. rN 10031, a 22 amino acid peptide, and analogues thereof will be tested for their ability to block PAI-I 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 rN 10031 peptide critical for its antagonist activity. Specific, potent TGF-beta antagonists offer the potential for development of a new class of drugs which regulate fibrinolysis.Awardee's statement of the potential commercial applications of the research:The research offers potential commercial applications in the development of a novel class of compounds which might have utility as adjunctive therapy to current thrombolytics or as therapeutic drugs to lower PAI-I levels in patients who are at potentially increased risk of myocardial infarction.National Heart, Lung and Blood Institute (NHLBI)
