PEPTIDE ANTAGONISTS TO TGF-BETA AS ANTITHROMBOTIC AGENTS

描述：(改编自申请人的摘要。)纤溶酶原 激活物抑制物-1(PAI-1)被认为是一种潜在的危险因素 心肌梗死因子及其药理作用的抑制 溶栓治疗。转化生长因子-β(TGF-β)是一种主要的 血小板裂解产物的成分，诱导血管释放PAI-1 内皮细胞。拟议研究的长期目标是 转化生长因子-β多肽拮抗剂的研制及其在临床中的应用 药物溶栓和/或慢性治疗的辅助治疗 PAI-1水平升高的患者。具体地说，建议的 研究将：1)证实转化生长因子-β的多肽拮抗剂rN10031， 抑制转化生长因子-β诱导的血管内皮细胞释放PAI-1， 和2)确定对rN10031至关重要的结构/活性关系 将允许其活动的最优化。RN10031是一个由22个氨基酸组成的多肽， 及其类似物将被测试其阻断PAI-1的能力 人血管内皮细胞释放(免疫化学测定) 用不同浓度的人血小板衍生的转化生长因子-β刺激。 将准备大约30个类似物来鉴定 RN10031多肽对其拮抗活性至关重要。据称， 特定的、有效的转化生长因子-β拮抗剂提供了开发的潜力 一种新型的调节纤溶的药物。

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.