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PROTOZOAN PURINE PHOSPHORIBOSYLTRANSFERASES AS TARGETS TO TREAT MALARIA, AFRICAN TRYPANOSOMIASIS AND CHAGAS'S DISEASE

原生动物嘌呤磷酸核糖基转移酶作为治疗疟疾、非洲锥虫病和恰加斯病的靶标

基本信息

批准号：
9449201
负责人：
Thomas Meek
金额：
$ 108.37万
依托单位：
TEXAS A&M AGRILIFE RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-25 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9449201
关键词：
Active Sites Adopted African African Trypanosomiasis Anabolism Animal Model Aotus primate Binding Bioavailable Catalysis Cell Culture Techniques Cells Central America Chagas Disease Chemistry Complex Crystallization Cultured Cells Development Development Plans Diphosphates Disease Drug Design Drug Kinetics Electrostatics Enzyme Inhibitor Drugs Enzymes Exhibits Gene Expression Gene Silencing Generations Genes Goals Gout Guanine HPRT1 gene Human Hypoxanthine Phosphoribosyltransferase Hypoxanthines In Vitro Infection Isotopes Kinetics Lead Malaria Maps Measurement Mediating Medical Methodology Molecular Molecular Conformation Molecular Target Morbidity - disease rate Mus Nucleosides Nucleotides Outcome Parasites Pathway interactions Permeability Pharmaceutical Preparations Phenotype Physiological Plasmodium Plasmodium falciparum Prodrugs Proteins Protozoa Purine Nucleosides Purine-Nucleoside Phosphorylase Purines Purinones Reaction Recombinants Reporting Research Ribose Roentgen Rays Sleep South America Specificity Structure Synthesis Chemistry T-Lymphocyte Technology Texas Therapeutic Agents Thermodynamics Time Toxic effect Transferase Treatment Efficacy Trypanosoma Trypanosoma brucei brucei Trypanosoma brucei gambiense Trypanosoma cruzi United States National Institutes of Health Vaccines Virulent X-Ray Crystallography Xanthines analog base chemical synthesis comparative computational chemistry design drug candidate drug development efficacy testing enzyme structure frontier human disease hypoxanthine-guanine-xanthine phosphoribosyltransferase in vivo inhibitor/antagonist inorganic phosphate metabolic phenotype mouse model nanomolar neglected tropical diseases next generation novel novel therapeutics pathogen phosphonate programs quantum computing safety testing serinol theories xanthosine monophosphate

项目摘要

PROJECT SUMMARY/ABSTRACT Parasitic protozoa rely on purine salvage pathways for which the enzyme hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT; hereafter, purine phosphoribosyltransferase (PPRT)) is essential. The genus Trypanosoma causes debilitating human diseases of high morbidity. Neither vaccines nor useful therapies exist. Trypanosoma cruzi causes Chagas’s Disease in Central and South America, with over 40 cases recently reported in Texas. Trypanosoma brucei rhodosiense and Trypanosoma brucei gambiense cause African sleeping sickness. Parasitic protozoa including T. cruzi and T. brucei are incapable of purine biosynthesis de novo and make nucleotides and nucleosides by purine salvage pathways. PPRT catalyzes the formation of GMP, IMP, and XMP from 5-phospho-ribose 1-pyrophosphate (PRPP) and the respective bases, guanine, hypoxanthine, and xanthine. Plasmodium falciparum, causes the most virulent form of malaria, and is also a purine auxotroph for which the action of PPRT is the only physiological path for hypoxanthine incorporation into the nucleotide pool. Transition-state analogue inhibitors (TSAIs) based on transition states for related phosphoribosyltransferases are inhibitors of P. falciparum PPRT. Cell-permeable prodrugs blocked the proliferation of P. falciparum in culture and showed selectivity vs. human HGPRT, despite the high structural similarity and active-site conservation of the enzymes. This research will design, synthesize, and characterize both in vitro and in vivo novel inhibitors of the PPRTs from P. falciparum, T. brucei ssp. and T. cruzi. Transition-state methodology, quantum computational chemistry, X-ray structure-based inhibitor design and expert chemical synthesis will be used for inhibitor development. Existing lead compounds of sub-nanomolar potency for PPRT from P. falciparum will initiate and inform our inhibitor program. Crystal structures have been reported for T. cruzi PPRT, but no potent inhibitors have been defined. No inhibitor development for T. brucei has been reported, and PPRTs have not been kinetically characterized from T. brucei. The generation of new lead compounds is anticipated to proceed rapidly for P. falciparum PPRT and emerge for Trypanosoma PPRTs once the transition-state structures of these enzymes have been solved. Optimized inhibitors which bind each of the target PPRTs will be evaluated by X-ray crystallography, to provide a refinement guide for chemistry. Potent and selective (vs. human HGPRT) inhibitors of the PPRTs will be evaluated in cell cultures of P. falciparum, T. cruzi, and T. brucei ssp for parasiticidal activity. The most effective of these will be evaluated in murine models of Malaria, Chagas’s disease and African sleeping sickness. Importantly, a successful outcome from this proposal could lead to new therapeutic agents to treat three diseases which comprise unmet or under-met medical needs. This development plan uses transition state theory to meet the NIH goals of reducing the lead time for drug development.

项目概要/摘要寄生原生动物依赖嘌呤补救途径，其中次黄嘌呤-鸟嘌呤-黄嘌呤酶磷酸核糖转移酶（HGXPRT；以下称为嘌呤磷酸核糖转移酶（PPRT））是必需的。这锥虫属导致高发病率的使人衰弱的人类疾病。疫苗也没用治疗方法是存在的。克氏锥虫在中美洲和南美洲引起恰加斯病，导致 40 多种德克萨斯州最近报告了病例。布氏罗多西锥虫和布氏冈比亚锥虫导致非洲昏睡病。包括克氏锥虫和布氏锥虫在内的寄生原生动物不能产生嘌呤从头生物合成并通过嘌呤补救途径制造核苷酸和核苷。 PPRT 催化从5-磷酸核糖1-焦磷酸（PRPP）和各自的碱基形成GMP、IMP和XMP，鸟嘌呤、次黄嘌呤和黄嘌呤。恶性疟原虫引起最致命的疟疾，并且是也是嘌呤营养缺陷型，PPRT 的作用是次黄嘌呤的唯一生理途径并入核苷酸库。基于过渡态的过渡态类似物抑制剂（TSAI）相关的磷酸核糖基转移酶是恶性疟原虫 PPRT 的抑制剂。细胞渗透性前药被阻断恶性疟原虫在培养物中的增殖，并显示出相对于人类 HGPRT 的选择性，尽管酶的结构相似性和活性位点保守性。本研究将设计、合成和表征 PPRT 的新型体外和体内抑制剂来自恶性疟原虫、布氏疟原虫亚种。和T.克鲁兹。过渡态方法、量子计算化学、基于X射线结构的抑制剂设计和专家化学合成将用于抑制剂发展。来自恶性疟原虫的 PPRT 亚纳摩尔效力的现有先导化合物将引发并告知我们的抑制剂计划。克氏锥虫 PPRT 的晶体结构已有报道，但没有有效的抑制剂已被定义。尚未有关于布氏锥虫抑制剂开发的报道，且 PPRT 尚未被报道。 T. brucei 的动力学特征。预计新的先导化合物的产生将继续进行一旦恶性疟原虫 PPRT 的过渡态结构出现，就会迅速出现锥虫 PPRT。这些酶已经被解决了。将评估与每个目标 PPRT 结合的优化抑制剂通过 X 射线晶体学，为化学提供改进指南。有效且有选择性（与人类相比） HGPRT） PPRT 抑制剂将在恶性疟原虫、克氏锥虫和布氏锥虫亚种的细胞培养物中进行评估用于杀寄生虫活性。其中最有效的方法将在疟疾、恰加斯氏病小鼠模型中进行评估病和非洲昏睡病。重要的是，该提案的成功结果可能会带来新的成果治疗包括未满足或未满足医疗需求的三种疾病的治疗剂。这开发计划使用过渡态理论来实现 NIH 缩短药物交付周期的目标发展。