Medical Structural Genomics of Pathogenic Protozoa (MSGPP)

致病性原生动物医学结构基因组学 (MSGPP)

• 批准号: 7216835
• 负责人: WILHELMUS G. J. HOL
• 金额: $ 224.88万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7216835
• 关键词: Medical; Structural; Genomics; Pathogenic; Protozoa

DESCRIPTION (provided by applicant): Ten major pathogenic protozoa form a serious threat to the well-being of humankind. There is a desperate need for new medicines for treating infected patients and for use as prophylaxis. The proposed interdisciplinary MSGPP Program Project will accelerate anti-protozoan drug development by: (i) Analyzing the genomes sequences from the targeted protozoa for suitable MSGPP protein targets from a functional and ligand perspective; (ii) Expressing, crystallizing and determining three-dimensional structures of the selected crucial proteins, focusing on complexes with small molecule ligands; (iii) Applying computational processes to these structures to predict new ligands targeting key sites of the selected proteins; (iv) Discovering in solution small molecule ligands binding to target proteins; (v) Using such ligands for the development of new leads and drug candidates, in collaboration with interested institutions. Protein targets will be selected from the following pathogenic protozoa: Plasmodium falciparum, Plasmodium vivax, Trypanosoma brucei, Trypanosoma cruzi, Leishmania major, Leishmania infantum, Entamoeba histolytica, Giardia lamblia, Cryptosporidium parvum, and Toxoplasma gondii. All of these organisms are the subject of ongoing or completed Genome Sequencing Projects. The last four pathogens are BIAID Category B Biodefense organisms. In the course of the three years duration of this Program Project, we estimate to obtain 428 soluble protein variants, representing 183 distinct target proteins, which will result in tree-dimensional structures of around 50 target proteins, plus about 250 target protein structures with ligands bound to them. This MSGPP Program Project includes four tightly integrated Projects and two Cores. We have a unique prior experience, as members of the Structural Genomics of Pathogenic Protozoa (SGPP) consortium, to perform the proposed research.

描述（由申请人提供）：十种主要的致病原生动物对人类的福祉构成严重威胁。迫切需要新的药物来治疗受感染的病人和用作预防。拟议的跨学科MSGPP计划项目将通过以下方式加速抗原生动物药物的开发：（i）从功能和配体的角度分析来自靶向原生动物的基因组序列，以寻找合适的MSGPP蛋白靶点;（ii）表达、结晶和确定所选关键蛋白质的三维结构，重点是与小分子配体的复合物;（iii）将计算过程应用于这些结构，以预测靶向所选蛋白质的关键位点的新配体;（iv）在溶液中发现与靶蛋白结合的小分子配体;（v）与感兴趣的机构合作，使用此类配体开发新的先导化合物和候选药物。蛋白质靶标将选自以下致病性原生动物：恶性疟原虫、间日疟原虫、布氏锥虫、克氏锥虫、硕大利什曼原虫、婴儿利什曼原虫、溶组织内阿米巴、贾第虫、微小隐孢子虫和刚地弓形虫。所有这些生物体都是正在进行或已完成的基因组测序项目的主题。最后四种病原体是BIAID类别B生物防御生物。在该计划项目的三年期间，我们估计将获得428种可溶性蛋白变体，代表183种不同的靶蛋白，这将导致约50种靶蛋白的三维结构，加上约250种靶蛋白结构与配体结合。该MSGPP计划项目包括四个紧密集成的项目和两个核心。作为病原性原生动物结构基因组学（SGPP）联盟的成员，我们在执行拟议的研究方面拥有独特的经验。