Toxoplasma Adenosine Kinase & Chemotherapy

弓形虫腺苷激酶

基本信息

批准号：
7257861
负责人：
Mahmoud H el Kouni
金额：
$ 49.87万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7257861
关键词：
4-nitrobenzylthioinosine 6-benzylthioinosine Abbreviations Active Sites Adenosine Kinase Adverse effects Binding Biology Cells Characteristics Chemicals Chemistry Collaborations Crystallization Development Enzymes Equilibrative-Nucleoside Transporter 2 Evaluation Goals HIV Human In Vitro Incidence Individual Infection Investigation Kinetics Laboratories Longevity Metabolic Metabolic Pathway Metabolism Molecular Morbidity - disease rate Mus Nature Numbers Opportunistic Infections Organism Parasites Patients Pattern Pharmaceutical Preparations Population Protein Overexpression Protozoa Purine Nucleosides Purines Purpose Research Personnel Resolution Site Specificity Staging Structure Structure-Activity Relationship Substrate Specificity Supervision Testing Therapeutic Agents Therapeutic Uses Toxic effect Toxoplasma Toxoplasma gondii Toxoplasmosis USA Georgia Universities Vidarabine Western Asia Georgia analog base chemical genetics chemical synthesis chemotherapy comparative design gene cloning hypoxanthine-guanine-xanthine phosphoribosyltransferase improved in vivo killings molecular modeling mortality mouse model mutant novel novel therapeutics pathogen programs purine purine analog purine metabolism research study success therapeutic target three dimensional structure uptake

项目摘要

DESCRIPTION (provided by applicant): Morbidity and mortality due to infections with Toxoplasma gondii is an increasing problem in the HIV infected population. Management of toxoplasmosis in these patients is complicated by a high incidence of side effects with the most commonly used compounds and the inactivity of these compounds against the latent stage of the parasite. Hence, there is a continuing need to define novel therapeutic targets and develop new therapeutic agents for this pathogen. One feature of the basic metabolism of these organisms which has not been fully exploited for chemotherapy is the characteristics of their adenosine kinase and its unique specificity in the activation of "subversive" substrates". Results from our laboratory indicate that the parasite, but not the host, adenosine kinase can uniquely phosphorylate certain 6-substituted purine nucleosides as "subversive" substrates and thereby selectively kill T. gondii in vitro and extend the life span of infected mice. Therefore, T. gondii adenosine kinase was cloned, overexpressed and purified. Structure activity relationships as well as comparative metabolic and molecular studies indicate that T. gondii adenosine kinase is indeed substantially different from that of the host in substrate specificity, structure and other characteristics. The purpose of this application is to extend our studies to further characterize the T. gondii adenosine kinase and to use the information gained to develop potent and selective subversive substrates as potential anti-toxoplasmic agents. This approach may well apply to other opportunistic infections which share with toxoplasma this unique feature of purine analogue metabolism. The Specific Aims are: Aim 1: Detailed studies of the cloned T. gondii adenosine kinase. Aim 2: Crystallization and resolution of the three dimensional structures of the enzyme with bound 6-substituted subversive substrates. Aim 3. Molecular modeling studies for the rational design of 6-substituted subversive substrates. Aim 4: Chemical synthesis and enzymatic evaluation of rationally designed 6-substituted subversive substrates. Aim 5: Evaluate promising rationally designed 6-substituted subversive substrates as potential anti-toxoplasmosis agents in vitro and in vivo. Aim: 6. Determine the mechanism of selective toxicity of active compounds. These studies will utilize the complementary strengths of the investigators in a collaborative, integrated effort to achieve these goals.

描述（由申请人提供）：弓形虫感染引起的发病率和死亡率是HIV感染人群的越来越多的问题。这些患者中毒质剂的治疗与最常用的化合物的副作用高发生率以及这些化合物相对于寄生虫的潜在阶段的不活跃而变得复杂。因此，持续需要定义新的治疗靶标并为该病原体开发新的治疗剂。这些生物的基本代谢的一个特征是尚未完全利用化学疗法的一个特征是它们的腺苷激酶的特征及其在激活“颠覆性的“底物”中的独特特异性。我们的实验室的结果表明，寄生虫表明寄生虫，但不是宿主，但不是宿主的腺苷激酶，腺苷激酶的某些含磷酸化的粉刺，并属于某些含磷酸化，并属于某些含量，并属于某些粉状蛋白酶，并属于某些含量呈磷酸化，并属于磷酸化的含量，并不有选择地杀死gondii的体外，并延长了被感染的小鼠的寿命。表征T. gondii腺苷激酶，并使用所获得的信息来发展有效和选择性的颠覆性底物作为潜在的抗毒剂。这种方法很可能适用于与弓形虫共享的其他机会性感染，这种嘌呤模拟代谢的独特特征。具体目的是：目标1：克隆的巨型链球菌腺苷激酶的详细研究。 AIM 2：具有绑定的6个取代的颠覆底物的酶的三维结构的结晶和分辨率。 AIM 3。用于6叠取代的颠覆底物的合理设计的分子建模研究。 AIM 4：对合理设计的六个稳定的颠覆底物的化学合成和酶促评估。 AIM 5：评估有前途的合理设计的6叠层颠覆底物作为体外和体内潜在的抗氧质体病。目的：6。确定活性化合物选择性毒性的机理。这些研究将利用研究人员的互补优势，以实现这些目标的协作，综合的努力。