The Dimeric Dutpase of Trypanosoma brucei as a therapeutic target
布氏锥虫二聚体脱氨酶作为治疗靶点
基本信息
- 批准号:10362613
- 负责人:
- 金额:$ 23.07万
- 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:2021-03-02 至 2023-10-31
- 项目状态:已结题
- 来源:
- 关键词:2&apos-DeoxythymidineAffectAffinityAfrican TrypanosomiasisAntiparasitic AgentsBindingBiochemicalBiological AssayBiologyCaringCell Culture TechniquesCell CycleCellsClinicalCommunicable DiseasesCrystallizationCytostaticsDNADNA DamageDNA RepairDNA biosynthesisDNA lesionDefectDevelopmentDiseaseDockingDrug TargetingEngineeringEnzymesEtiologyEventExcisionFluorouracilGenomeGenomic DNAGoalsGrowthHealthHumanKineticsKnowledgeLaboratoriesLeadLesionLigandsMediatingMetabolic PathwayMetabolismMethodsMethotrexateMissionOrganismParasitesPathogenicityPathway interactionsPentamidinePharmaceutical PreparationsPharmacologyProductionProteinsProtozoan InfectionsPublic HealthRecombinantsRegimenResearchResolutionSiteStructural BiochemistryStructureSystemTherapeutic IndexThymidineToxic effectTrypanocidal AgentsTrypanosomaTrypanosoma brucei bruceiUnited States National Institutes of HealthUracilWorkYeastsbasecancer therapycellular targetingcombatcytotoxiccytotoxicitydUTP pyrophosphatasedesigndimerefficacy testinggenome integritygenotoxicityglobal healthhigh riskimprovedinsightinterestmortalitynovelnovel strategiesnucleotide metabolismpathogenpreventprogramsscreeningsmall moleculesmall molecule inhibitortargeted agenttherapeutic targettripolyphosphatevirtualvirtual screeningyeast geneticsyeast protein
项目摘要
PROJECT SUMMARY
Trypanosoma Brucei is a protozoan parasite and a pathogen responsible for the Human African
Trypanosomiasis (HAT), or “sleeping sickness”. HAT and other diseases caused by closely related
pathogenic parasites represent a substantial global health concern, especially because there is a
limited choice of effective antiparasitic drugs. Recent discovery that the dUTP pyrophosphatase
(dUTPase) enzyme in T. brucei is significantly divergent from that of human or other mammalian
systems has heightened the interest in this enzyme as a possible anti-parasitic drug target. dUTPase
is an essential protein in most known living forms; it is required for the synthesis of deoxythymidine
triphosphate (dTTP) in support of DNA replication and for limiting the incorporation of uracil into
genomic DNA to reduce the detrimental DNA breaks initiated by uracil glycosylase. In the long term,
the goal is to develop an effective anti-trypanosome drug with limited toxicity and high therapeutic index.
The specific objective of this proposal is to identify and characterize small molecules that are cytotoxic
to T. brucei by inhibition of the dUTPase activity in the following two specific aims. In Aim1, we will take
two complementary approaches to identify candidate small molecules targeting T. brucei dUPTase. As
an extension of the comprehensive work into the mechanism of uracil DNA incorporation carried out in
our laboratory, we designed a cell-based assay where T. brucei or human dUTPase functionally
replaces the yeast protein. Using this system, we will screen for molecules differentially inhibiting the
growth of yeast cells expressing T. brucei dUTPase and not the cells expressing the human enzyme.
Additionally, through the use of virtual docking program, we will identify molecules binding with high
affinity to T. brucei but not human dUTPase. In Aim2, the cytotoxic effect of the candidate molecules
will be further characterized in yeast and T. brucei cultures. We will also confirm that, as expected from
the disruption of dUTP->dTTP metabolic pathway, the cytotoxicity is correlated with the elevated level
of uracil in DNA, DNA breaks, and cell-cycle defect. The significance of the proposed research is
underscored by its significant potential to provide further insight into the mechanism of anti-parasitic
drugs that target the cellular dUTP/dTTP metabolism and finally a mechanistic basis for the improved
efficacy of the combination chemotherapeutic regimen against HAT and other related diseases.
项目总结
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Yeast transcription factor Msn2 binds to G4 DNA.
- DOI:10.1093/nar/gkad684
- 发表时间:2023-10-13
- 期刊:
- 影响因子:14.9
- 作者:Duy, Duong Long;Kim, Nayun
- 通讯作者:Kim, Nayun
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Nayun Kim其他文献
Nayun Kim的其他文献
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{{ truncateString('Nayun Kim', 18)}}的其他基金
Mechanism of transcription-associated genome instability
转录相关基因组不稳定的机制
- 批准号:
10592934 - 财政年份:2021
- 资助金额:
$ 23.07万 - 项目类别:
Mechanism of transcription-associated genome instability
转录相关基因组不稳定的机制
- 批准号:
10797547 - 财政年份:2021
- 资助金额:
$ 23.07万 - 项目类别:
Mechanism of transcription-associated genome instability
转录相关基因组不稳定的机制
- 批准号:
10207038 - 财政年份:2021
- 资助金额:
$ 23.07万 - 项目类别:
Mechanism of transcription-associated genome instability
转录相关基因组不稳定的机制
- 批准号:
10810267 - 财政年份:2021
- 资助金额:
$ 23.07万 - 项目类别:
Mechanism of transcription-associated genome instability
转录相关基因组不稳定的机制
- 批准号:
10474278 - 财政年份:2021
- 资助金额:
$ 23.07万 - 项目类别:
Mechanism of transcription-associated genome instability
转录相关基因组不稳定的机制
- 批准号:
10649647 - 财政年份:2021
- 资助金额:
$ 23.07万 - 项目类别:
G-Quadruplex forming sequence motifs and genome instability
G-四链体形成序列基序和基因组不稳定性
- 批准号:
9889136 - 财政年份:2016
- 资助金额:
$ 23.07万 - 项目类别:
G-Quadruplex forming sequence motifs and genome instability
G-四链体形成序列基序和基因组不稳定性
- 批准号:
9103794 - 财政年份:2016
- 资助金额:
$ 23.07万 - 项目类别:
G-Quadruplex forming sequence motifs and genome instability
G-四链体形成序列基序和基因组不稳定性
- 批准号:
9247232 - 财政年份:2016
- 资助金额:
$ 23.07万 - 项目类别:
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