PEPTIDE ANTAGONISTS TO TGF-BETA AS ANTITHROMBOTIC AGENTS

描述：（改编自申请人的摘要。）酶原 激活物抑制剂-1（派-1）被认为是潜在的风险 心肌梗死因子和作为药理学抑制剂 血栓溶解 转化生长因子-β（TGF-β），一种主要的 血小板裂解物的成分，诱导派-1从血管释放 内皮细胞 拟议研究的长期目标是 开发TGF-β的肽拮抗剂并验证其用于 药物溶栓和/或长期治疗的后续治疗 派-1水平升高的患者。 具体而言，建议 研究将：1）证实rN 10031，一种TGF-β的肽拮抗剂， 抑制TGF-β诱导的派-1从血管内皮细胞释放， 和2）鉴定对rN 10031至关重要的结构/活性关系， 将允许优化其活动。 rN 10031，22个氨基酸的肽， 将测试它们阻断派-1的能力 从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TGF-β刺激。 将制备大约30种类似物以鉴定 rN 10031肽对于其拮抗剂活性至关重要。 据称， 特异性、有效的TGF-β拮抗剂为开发 一种新型的调节纤维蛋白溶解的药物。

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.