DEVELOPING SELECTIVE CALPAIN INHIBITORS

开发选择性钙蛋白酶抑制剂

• 批准号: 2900977
• 负责人: Isaac O. Donkor
• 金额: $ 10.98万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2900977
• 关键词: active sites; affinity labeling; antithrombins; calpain; chemical synthesis; enzyme mechanism; mass spectrometry; peptide chemical synthesis; protease inhibitor; protein sequence

Dr. Donkor obtained the Ph.D. Degree in 1988 and had one year of postdoctoral training at the University of North Carolina at Chapel Hill before joining the Faculty at Xavier University of Louisiana (XU) from 1989 to 1993. At XU his research productivity was minimal due to heavy teaching assignments. In August of 1993 he joined the University of Tennessee (UT). At UT, with adequate release time at his disposal, he has published five peer reviewed articles within the two years he has been there. This clearly demonstrates. Dr. Donkor's interest in research. He hopes to develop research capabilities in i) advanced medicinal chemistry (peptide synthesis, SAR, affinity labeling of enzymes, and molecular modeling); ii) analytiCal chemistry (chromatographiC techniques such as RP-HPLC, mass spectrometry, and gel electrophoresis); and iii) enzymology (protein assay, and enzyme assay). He will develop these capabilities through hands-on research aimed at discovering potent selective inhibitors of calpain which will be studied in future as antithrombotic agents. Thrombin-induced platelet aggregation plays an important role in reocclusion following: thrombolytic therapy or angioplasty for treatment of myocardial infarction. It has been demonstrated that thrombin-induced platelet aggregation is indirectly mediated by intracellularly activated calpain expressed on the platelet surface through the cleavage of aggregin, a putative ADP-receptor. Selective calpain inhibitors are therefore of interest as antithrombotic agents. The long-term goal of the proposed research is to characterize the active site of calpain with the intention of developing potent selective inhibitors of calpain for preventing the initiation and/or propagation of thrombus formation. The specific aims are: i) to identify the amino acid sequence at the active site of calpain to which inhibitors bind via affinity labeling; and ii) to synthesize compounds that will allow us to characterize the active site of calpain.

Donkor 博士获得博士学位。 1988年获得学位并学习了一年 北卡罗来纳大学教堂山分校博士后培训 加入路易斯安那泽维尔大学 (XU) 之前 1989 年至 1993 年。在徐大，他的研究成果由于繁重的工作而微乎其微。 教学作业。 1993年8月，他加入了大学。 田纳西州（UT）。在 UT，他有足够的释放时间， 在他任职的两年内发表了五篇同行评审的文章 那里。这清楚地表明了。 Donkor 博士对研究的兴趣。他 希望发展 i) 先进药物化学方面的研究能力 （肽合成、SAR、酶的亲和标记和分子 造型）; ii) 分析化学（色谱技术，例如 RP-HPLC、质谱和凝胶电泳）； iii) 酶学 （蛋白质测定和酶测定）。他将发展这些能力 通过旨在发现有效选择性抑制剂的实践研究 钙蛋白酶，将来将作为抗血栓剂进行研究。 凝血酶诱导的血小板聚集在以下过程中起重要作用： 再闭塞如下：溶栓治疗或血管成形术治疗 心肌梗塞。 已经证明，凝血酶诱导 血小板聚集是由细胞内活化的间接介导的 钙蛋白酶通过裂解在血小板表面表达 聚集蛋白，一种假定的 ADP 受体。选择性钙蛋白酶抑制剂是 因此作为抗血栓剂受到关注。该组织的长期目标 拟议的研究是表征钙蛋白酶的活性位点 开发有效的选择性钙蛋白酶抑制剂的意图 防止血栓形成的引发和/或传播。这 具体目标是： i) 鉴定活性位点的氨基酸序列 抑制剂通过亲和标记结合的钙蛋白酶位点； ii) 至 合成化合物，使我们能够表征活性位点 钙蛋白酶。