SYNTHETIC CHEMISTRY

合成化学

• 批准号: 6816899
• 负责人: WILLIAM R ROUSH
• 金额: $ 19.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6816899
• 关键词: X ray crystallography; antiparasitic agents; cysteine endopeptidases; drug design /synthesis /production; enzyme structure; nuclear magnetic resonance spectroscopy; peptide analog; protease inhibitor

The overall aim of this research program is to develop novel, potent and highly selective inhibitors of cruzain, the major cysteine protease of Trypanosoma cruzi; falcipain-2 and -3, the major cysteine proteases of the Plasmodium falciparum trophozoite; rhodesain from Trypanosoma brucei rhodesiense; and the cathepsin B-like (Lmaicatb) and L-like cysteine proteases from Leishmania major. Efforts will be made to develop a single cysteine protease inhibitor that is effective against all of the targeted parasites. Specific aims for the next grant period include: (1) Optimization of the vinyl sulfonyl inhibitor P' substituent. (2) Development of a solid-phase synthesis of vinyl sulfonyl inhibitors. (3) Continued development and optimization of E-64 analogs. (4) Development of conformationally constrained cysteine protease inhibitors. (5) Development of heterocycle-based peptidometics as cysteine protease inhibitors. (6) Determination of enzyme-bound inhibitor conformations and active site structures via transferred Nuclear Overhauser Effect (TRNOE) and residual dipolar coupling studies. (7) NMR screening of new inhibitor scaffolds. All enzymatic and biological evaluation of the inhibitors will be performed at UCSF (McKerrow for cruzain, rhodesain and the leishmania enzymes; Rosenthal for falcipains-2 and -3). To the extent possible, the best inhibitors will be characterized by X-ray analysis of the inactivated enzyme. Inhibitor complexes of the targeted proteases that have not yielded to crystallographic analysis will be characterized by NMR methods.

本研究计划的总体目标是开发新的，有效的和高选择性的抑制剂cruzain，主要的半胱氨酸蛋白酶的克氏锥虫; falcipain-2和-3，主要的半胱氨酸蛋白酶的恶性疟原虫滋养体; rhodesain从布氏锥虫罗得西亚;和组织蛋白酶B样（Lmaicatb）和L样半胱氨酸蛋白酶从利什曼原虫。将努力开发一种单一的半胱氨酸蛋白酶抑制剂，对所有的目标寄生虫有效。下一个资助期的具体目标包括： (1)乙烯基磺酰基缓蚀剂P'取代基的优化。 (2)乙烯基磺酰基缓蚀剂的固相合成研究。 (3)继续开发和优化E-64类似物。 (4)构象限制型半胱氨酸蛋白酶抑制剂的研究进展。 (5)半胱氨酸蛋白酶抑制剂的杂环基肽组学研究进展。 (6)酶结合抑制剂构象和活性位点结构的测定 转移核Overhauser效应（TRNOE）和残留偶极耦合研究。 (7)新抑制剂支架的NMR筛选。 抑制剂的所有酶和生物学评价将在加州大学旧金山分校（McKerrow， cruzain，rhodesain和利什曼原虫酶; Rosenthal用于恶性疟原虫蛋白酶-2和-3）。在可能的范围内，最好的抑制剂将通过失活酶的X射线分析来表征。将通过NMR方法表征尚未进行晶体学分析的靶向蛋白酶的抑制剂复合物。