STRUCTURE AND FUNCTION OF REGION 11-PLUS OF THE CS PROTEIN

CS 蛋白 11-PLUS 区的结构和功能

• 批准号: 3747589
• 负责人: VICTOR NUSSENZWEIG
• 金额: --
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3747589
• 关键词: Coccidia; Plasmodium berghei; binding proteins; cell membrane; chemical kinetics; circular dichroism; electron microscopy; fluorescence microscopy; heparan sulfate; laboratory mouse; liver cells; malaria; mass spectrometry; monoclonal antibody; nuclear magnetic resonance spectroscopy; protein metabolism; protein structure function; proteoglycan; protozoal infection; receptor binding; synthetic peptide

The long term objectives of this application are to define the mechanisms involved in invasion of hepatocytes by sporozoites and to develop specific inhibitors. Our specific aims are: (1) to analyze the structural requirements for the recognition of region II-plus of the CS by heparan sulfate proteoglycan (HSPG) receptors on hepatocytes; (2) to study in mice the role of region II-plus in the clearance and fate of intravenously injected CS, and determine whether injected synthetic peptides representing region II-plus are targeted to hepatocytes; (3) to inhibit malarial infection in vitro and in vivo by preventing the recognition of sporozoite CS by the HSPG hepatocyte receptors. This will be attempted by competitive inhibition with region II-plus synthetic peptides. Because the region II-plus motif is found in other parasite proteins, in thrombospondin, properdin, the terminal complement components C6 through C9, F-spondin and UNC-5 (molecules involved in the development of the nervous system), the characterization of the region II-plus motif should have applications outside the malaria field. The results of these studies will be of relevance to the development of immunoprophylactic agents and drugs to treat malaria infection. Small molecule mimetic drug engineering is an emerging strategy in pharmaceutical research. In particular, the peptidomimetic approaches (including the design of conformationally restricted peptides), based on molecular modeling, have already been used to probe receptor biology and to create beta-turn mimics. Our studies may also have practical applications in gene therapy: it is conceivable that the specificity of region II-plus of CS for hepatocytes can be utilized to deliver genetic information to these cells in vivo.

此应用程序的长期目标是定义机制 参与孢子虫对肝细胞的侵袭并开发特定 抑制剂。 我们的具体目的是：（1）分析结构 识别乙酰肝素CS的II-II-II-II-pure的要求 肝细胞上的硫酸盐蛋白聚糖（HSPG）受体； （2）在小鼠中学习 II-Plus的作用在静脉注射的清除和命运中 注射CS，并确定是否注入了代表的合成肽 II-Plus靶向肝细胞； （3）抑制疟疾 通过预防孢子岩的识别，体外感染和体内感染 HSPG肝细胞受体的CS。 这将由竞争力尝试 II-Plus合成肽的抑制作用。 因为在其他寄生虫蛋白中发现了区域II-Plus基序，所以 血小板传播，适当丁，终端补体组件C6通过 C9，F-Spondin和UNC-5（参与发展的分子 神经系统），II-Plus基序的表征应 在疟疾领域外有申请。 这些研究的结果 将与免疫原性药物的发展有关 治疗疟疾感染的药物。 小分子模拟药物工程 是药物研究中的新兴策略。 特别是 肽型方法（包括构象的设计 基于分子建模的受限肽）已经被使用 探测受体生物学并创建beta-turn模仿。 我们的研究可能 在基因疗法中也有实际应用：可以想象 CS区域II-Plus的特异性可用于用于肝细胞 在体内向这些细胞传递遗传信息。