Medical Structural Genomics of Pathogenic Protozoa (MSGPP)

描述(申请人提供)：十种主要致病原虫对人类福祉构成严重威胁。迫切需要新的药物来治疗感染患者并用于预防。拟议的跨学科MSGPP计划项目将通过以下方式加速抗原虫药物的开发：(I)从功能和配体的角度分析目标原虫的基因组序列，以寻找合适的MSGPP蛋白质靶标；(Ii)表达、结晶和确定选定的关键蛋白质的三维结构，重点是小分子配体的复合体；(Iii)将计算过程应用于这些结构，以预测针对选定蛋白质关键位置的新配体；(Iv)在溶液中发现与目标蛋白质结合的小分子配体；(V)与感兴趣的机构合作，利用这些配体开发新的先导和候选药物。蛋白质靶标将从下列致病原虫中选择：恶性疟原虫、间日疟原虫、布氏锥虫、克氏锥虫、大利什曼原虫、婴儿利什曼原虫、溶组织内阿米巴、蓝氏贾第鞭毛虫、微小隐孢子虫和弓形虫。所有这些生物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 B类生物防御生物。在这个项目为期三年的过程中，我们估计获得了428个可溶性蛋白质变体，代表183个不同的目标蛋白质，这将导致大约50个目标蛋白质的三维结构，以及大约250个带有配体的目标蛋白质结构。该MSGPP计划项目包括四个紧密集成的项目和两个核心。作为致病原生动物结构基因组学(SGPP)联盟的成员，我们有独特的先前经验来执行拟议的研究。

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.