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: 7027907
• 负责人: WILHELMUS G. J. HOL
• 金额: $ 223.25万
• 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/7027907
• 关键词: antiprotozoal agents; chemical structure function; drug discovery /isolation; protein structure function; proteomics; protozoa; structural biology

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福祉构成了严重威胁。迫切需要新药物来治疗感染患者并用作预防。拟议的跨学科MSGPP计划项目将通过：（i）分析来自靶向原生动物的基因组序列，从功能和配体角度分析合适的MSGPP蛋白靶标的基因组序列； （ii）表达，结晶和确定所选关键蛋白的三维结构，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，以预测针对所选蛋白质关键位点的新配体； （iv）在溶液中发现小分子配体与靶蛋白结合； （v）与有兴趣的机构合作，使用此类配体来开发新的铅和候选者。蛋白质靶标将从以下致病原生动物中选择：恶性疟原虫，疟原虫，疟原虫Brucei，Brucei，Cruzi，Leishmania Major，Leishmania Invantum，Entamoeba Histolodytica，Leishmania solytica，Lamblia lamblia lamblia，Cryptososporidium Porporidium Parvum和gondiium Parvum，gondium gondium gondiium gondiium gondimmammammammammammammammammammammammammammammamma。所有这些生物都是正在进行或完成的基因组测序项目的主题。最后四种病原体是BIAID类Biodefense生物。在该计划项目的三年持续时间内，我们估计获得428种可溶性蛋白质变体，代表183个不同的靶蛋白，这将导致大约50个靶蛋白的树维结构，加上大约250个靶标蛋白质结构带有配体的靶蛋白结构绑定到他们。这个MSGPP计划项目包括四个紧密整合的项目和两个核心。作为致病原生动物（SGPP）联盟的结构基因组学的成员，我们具有独特的先前经验，以进行拟议的研究。