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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：
9767013
负责人：
Thomas Meek
金额：
$ 101.4万
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/9767013
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.

项目总结/文摘