Development of small molecule inhibitors of metabolic enzymes as broad spectrum anthelmintic drugs
开发小分子代谢酶抑制剂作为广谱驱虫药
基本信息
- 批准号:10581534
- 负责人:
- 金额:$ 77.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-03-11 至 2026-02-28
- 项目状态:未结题
- 来源:
- 关键词:AccelerationActive SitesAddressAdultAffectAffinityAncylostoma (genus)Animal ModelAnthelminticsAreaBasic ScienceBiochemicalBiochemical PathwayBioinformaticsBiologicalBiological AssayCarnitineClinicalConsumptionDataDatabasesDevelopmentDimensionsDockingDrug DesignDrug KineticsDrug TargetingDrug resistanceEnzyme InhibitionEnzyme Inhibitor DrugsEnzymesEvaluationFRAP1 geneFormulationFundingGene Expression ProfilingGenerationsGenesGenomeGenomicsGoalsHamstersHomologous GeneHomology ModelingHookwormsHumanIn VitroInfectionInterventionIntestinesKnowledgeLabelLeadLifeMaintenanceMeasuresMetabolicMolecularMorbidity - disease rateMusNecator americanusNematodaNematode infectionsOrthologous GenePIK3CG geneParasitesParasitic nematodeParasitologyPathway interactionsPenetrationPersonsPharmaceutical ChemistryPharmaceutical PreparationsPharmacotherapyPhenotypePhosphotransferasesPhylogenyPovertyPropertyProteinsRecombinantsResearchRodent ModelRoentgen RaysSeriesStructureStructure-Activity RelationshipSystems BiologyTaxonomyTechniquesTestingTimeToxic effectTransferaseTranslational ResearchTrichurisUnited States National Institutes of HealthWorkbioaccumulationburden of illnessclinical candidatedesigndrug developmentdrug discoveryexperiencehuman morbidityimprovedin vivoin vivo evaluationinhibitorinnovationinterdisciplinary approachknock-downlead optimizationmortalitymultidisciplinarymutantnovelnovel therapeuticsparasitismpathogenphosphoric diester hydrolasepre-clinicalpublic health prioritiesrational designscreeningsmall moleculesmall molecule inhibitorsmall molecule therapeuticsspecies difference
项目摘要
Development of small molecule inhibitors of metabolic enzymes as broad spectrum anthelmintic drugs
Abstract
Parasitic intestinal nematodes including hookworms, roundworm and whipworms, infect over two billion people
worldwide, causing significant morbidity, perpetuation of poverty, and loss of life. Characterization of nematode
genomes provides fundamental molecular information essential for accelerating basic and translational research,
which is a public health priority due to the limited number of currently available effective drugs and increasing
drug resistance. In this proposal, we will pursue post-genomic drug discovery studies to develop small molecule
drugs as novel therapeutics to treat infections caused by these devastating parasites.
We have established an extensive omics/bioinformatics database for human nematode parasites
spanning the major taxonomic clades of Nematoda. Using systems biology and evolutionary principles, we
reconstructed metabolic networks for 56 diverse nematode parasites and identified chokepoint enzymes, i.e.
metabolic enzymes that uniquely consume a specific substrate or generate a unique product. This led to our
central hypothesis that compounds that inhibit conserved chokepoint enzymes have a strong potential for broad
control of diverse nematodes. To test this, we identified conserved targets and initial inhibitors with potential for
broad-spectrum activity, for which phenotypic screening of parasites at the extremes of the phylogeny have
validated our predictions. Furthermore, we established a unique database of nematode-specific molecular
features among the chokepoint enzyme targets and experimentally established that active-site differences in the
nematode enzymes relative to their human orthologs can rationally guide the design of selective inhibitors.
The compounds with the best activity in our phenotypic screens are inhibitors predicted to target three
known enzyme classes (CPT, mTOR/PI3K, and PDE). To confirm the putative nematode target(s), we will
express nematode proteins and implement biochemical enzyme inhibition assays, employ affinity-based labeling
techniques, and test for activity against target knockdown worms (Aim 1). By leveraging parasite-specific active-
site features of the confirmed protein targets, we will use a X-ray structure-based drug design (SBDD) to optimize
lead inhibitors of the three identified target classes (Aim 2). Optimized lead compounds most effective against
the human hookworm Ancylostoma ceylanicum and the whipworm Trichuris muris in vitro will be tested in vivo
for their pan-intestinal efficacy in hamster and mouse animal models of nematode infection (Aim 3).
Our preliminary results, combined with this proposed research, are highly significant since they provide
a better understanding of metabolic functions essential for nematode survival, which can be targeted for drug
discovery. The rational targeting of metabolic chokepoint enzymes as anthelminthic agents is innovative, as is
the concept of utilizing specific pan-phylum conserved targets to develop anthelmintic drug or drugs with broad
spectrum efficacy against nematodes. Collectively, this work has high potential to provide one or more new small
molecule therapeutics with broad spectrum activity against parasitic nematode infections.
代谢酶小分子抑制剂广谱驱虫药的研究进展
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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James W Janetka其他文献
James W Janetka的其他文献
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{{ truncateString('James W Janetka', 18)}}的其他基金
Innovative therapeutic strategies to support elimination of river blindness
支持消除河盲症的创新治疗策略
- 批准号:
10754120 - 财政年份:2023
- 资助金额:
$ 77.39万 - 项目类别:
Optimizing CDPK1 inhibitors for chronic toxoplasmosis
优化慢性弓形虫病的 CDPK1 抑制剂
- 批准号:
10457052 - 财政年份:2022
- 资助金额:
$ 77.39万 - 项目类别:
Optimizing CDPK1 inhibitors for chronic toxoplasmosis
优化慢性弓形虫病的 CDPK1 抑制剂
- 批准号:
10580799 - 财政年份:2022
- 资助金额:
$ 77.39万 - 项目类别:
Development of small molecule inhibitors of metabolic enzymes as broad spectrum anthelmintic drugs
开发小分子代谢酶抑制剂作为广谱驱虫药
- 批准号:
10370382 - 财政年份:2021
- 资助金额:
$ 77.39万 - 项目类别:
Rational design and synthesis of small molecule inhibitors targeting unique pathogenic mechanisms in Gram- and Gram+ bacteria important in UTI
针对尿路感染中重要的革兰氏菌和革兰氏菌独特致病机制的小分子抑制剂的合理设计和合成
- 批准号:
10352466 - 财政年份:2021
- 资助金额:
$ 77.39万 - 项目类别:
Integrative approach for accelerating filarial worm drug discovery to treat river blindness
加速丝虫药物研发以治疗河盲症的综合方法
- 批准号:
10478172 - 财政年份:2021
- 资助金额:
$ 77.39万 - 项目类别:
Development of small molecule inhibitors of metabolic enzymes as broad spectrum anthelmintic drugs
开发小分子代谢酶抑制剂作为广谱驱虫药
- 批准号:
10198436 - 财政年份:2021
- 资助金额:
$ 77.39万 - 项目类别:
Integrative approach for accelerating filarial worm drug discovery to treat river blindness
加速丝虫药物研发以治疗河盲症的综合方法
- 批准号:
10317958 - 财政年份:2021
- 资助金额:
$ 77.39万 - 项目类别:
Rational design and synthesis of small molecule inhibitors targeting unique pathogenic mechanisms in Gram- and Gram+ bacteria important in UTI
针对尿道感染中重要的革兰氏菌和革兰氏菌独特致病机制的小分子抑制剂的合理设计和合成
- 批准号:
10577800 - 财政年份:2021
- 资助金额:
$ 77.39万 - 项目类别:
Integrative approach for accelerating filarial worm drug discovery to treat river blindness
加速丝虫药物研发以治疗河盲症的综合方法
- 批准号:
10650810 - 财政年份:2021
- 资助金额:
$ 77.39万 - 项目类别:
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