SYNTHETIC CHEMISTRY

这项研究的总体目标是开发新的、有效的和高选择性的抑制物，包括克氏锥虫的主要半胱氨酸蛋白酶-克鲁赞、恶性疟原虫滋养体的主要半胱氨酸蛋白酶-2和-3、布氏锥虫的罗得辛，以及大利什曼原虫的组织蛋白酶B样(Lmaicatb)和L样半胱氨酸蛋白酶。将努力开发一种对所有目标寄生虫有效的半胱氨酸蛋白酶抑制剂。下一批赠款的具体目标包括： (1)乙烯基磺酰缓蚀剂P‘取代基的优化。 (2)开发固相合成乙烯基磺酰类抑制剂。 (3)继续开发和优化E-类比。 (4)构象受限半胱氨酸蛋白酶抑制剂的开发。 (5)杂环肽类化合物作为半胱氨酸蛋白酶抑制剂的开发。 (6)酶结合抑制物构象和活性部位结构的测定 转移核Overhauser效应(TRNOE)和剩余偶极耦合研究。 (7)新型缓蚀剂支架的核磁共振筛选。 所有抑制剂的酶学和生物学评估将在UCSF(McKerrow for 克鲁萨因、罗得森和利什曼原酶；罗森塔尔用于镰刀菌-2和-3)。在可能的范围内，最好的抑制剂将通过对失活的酶进行X射线分析来表征。目标蛋白水解酶的抑制剂复合体将通过核磁共振方法进行表征。

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.