CYSTEINE PROTEASE-INHIBITOR COMPLEXES; DESIGNING THERAPEUTICS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 建议的工作的基础是在选择性控制寄生虫病中蛋白水解作用的竞技场中提问和回答问题。我们的目标是了解蛋白水解酶的功能和调节，并利用结构生物学来指导有效的，特异性抑制剂的设计。为了实现这一点，我们使用生物化学和结构生物学技术？包括高分辨率X射线晶体学。正在研究的靶标包括与设计小分子抑制剂的目标相关的那些，所述小分子抑制剂将被优化以用于寄生虫感染的新治疗剂，并且源自以下生物体：来自克氏锥虫的cruzain和cruzipain 2、来自布氏锥虫罗得西亚的TbCatB、来自恶性疟原虫的falcipain 3、来自溶组织内阿米巴的EhCP 4和来自蓝氏贾第鞭毛虫的GlCP。由这些代理人引起的疾病分别是，南美锥虫病？疾病，非洲人锥虫病，疟疾，阿米巴结肠炎和贾第虫病。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The basis of the proposed work is to ask and answer questions in the arena of selective control of proteolytic action in parasitic disease. Our goal is to understand the function and regulation of proteolytic enzymes and to use structural biology to guide the design of potent, specific inhibitors. To achieve this, we use biochemical and structural biology technologies ? including high resolution x-ray crystallography. Targets under study include those pertinent to the goal of designing small molecule inhibitors to be optimized to new therapeutics for parasitic infection and are derived from the following organisms: cruzain and cruzipain 2, from Trypanosoma cruzi, TbCatB from Trypanosoma brucei rhodesiense, falcipain 3 from Plasmodium falciparum, EhCP4 from Entomeba histolytica and GlCP from Giardia lamblia. The diseases caused by these agents are, respectively, Chagas? disease, Human African Trypanosomiasis, malaria, amoebic colitis and giardiasis.