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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：
10223119
负责人：
Thomas Meek
金额：
$ 100.37万
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 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10223119
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 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 chemistry safety testing serinol theories therapeutically effective 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.

项目总结/摘要寄生原生动物依赖嘌呤补救途径，次黄嘌呤-鸟嘌呤-黄嘌呤酶磷酸核糖基转移酶（HGXPRT;以下称为嘌呤磷酸核糖基转移酶（PPRT））是必需的。的锥虫属引起高发病率的使人衰弱的疾病。既没有疫苗也没有用治疗是存在的。克氏锥虫在中美洲和南美洲引起查加斯病，最近在德克萨斯州报道的病例。布氏锥虫Rhodosiense和冈比亚锥虫引起非洲昏睡病。寄生原生动物包括T. cruzi和T.布鲁氏菌不能产生嘌呤通过嘌呤补救途径从头生物合成并产生核苷酸和核苷。PPRT催化由5-磷酸-核糖1-焦磷酸（PRPP）和相应的碱基形成GMP、IMP和XMP，鸟嘌呤、次黄嘌呤和黄嘌呤。恶性疟原虫是最致命的疟疾，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掺入到核苷酸库中。基于过渡态的过渡态类似物抑制剂相关的磷酸核糖基转移酶是恶性疟原虫PPRT的抑制剂。细胞渗透性前药阻断恶性疟原虫在培养物中的增殖，并显示出相对于人HGPRT的选择性，尽管高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的体外和体内新型抑制剂恶性疟原虫（P. falciparum）、T.布氏亚种和T.克鲁兹过渡态方法论，量子计算化学，X射线结构为基础的抑制剂设计和专家化学合成将用于抑制剂发展现有的针对恶性疟原虫PPRT的亚纳摩尔效力的先导化合物将启动并通知我们的抑制剂计划晶体结构已被报道的T。cruzi PPRT，但没有有效的抑制剂已被定义。对T.布氏杆菌已被报告，PPRT尚未被从T.布鲁塞。新的先导化合物的生产预计将继续进行恶性疟原虫PPRT和锥虫PPRT的出现，一旦过渡态结构这些酶已经被解决了。将评价结合每种靶PPRT的优化抑制剂通过X射线晶体学，为化学提供了一个完善的指导。有效和选择性（与人类相比将在恶性疟原虫、T. cruzi和T.布鲁氏菌杀寄生虫的活性其中最有效的将在疟疾的小鼠模型中进行评估，查加斯氏病非洲昏睡病和非洲昏睡病。重要的是，这一提议的成功结果可能会导致新的治疗三种疾病的治疗剂，包括未满足或未满足的医疗需求。这开发计划使用过渡态理论来满足NIH减少药物交付时间的目标发展

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The design of protozoan phosphoribosyltransferase inhibitors containing non-charged phosphate mimic residues.

含有不带电荷的磷酸盐模拟残基的原生动物磷酸核糖基转移酶抑制剂的设计。

DOI：
10.1016/j.bmc.2022.117038
发表时间：
2022
期刊：
Bioorganic & medicinal chemistry
影响因子：
3.5
作者：
Gai,Sinan;Suthagar,Kajitha;Shaffer,KarlJ;Jiao,Wanting;Minnow,YacobaVT;Glockzin,Kayla;Maatouk,SeanW;Katzfuss,Ardala;Meek,ThomasD;Schramm,VernL;Tyler,PeterC
通讯作者：
Tyler,PeterC

Characterization of adenine phosphoribosyltransferase (APRT) activity in Trypanosoma brucei brucei: Only one of the two isoforms is kinetically active.