Identification of preclinical drug candidates for the treatment of schistosomiasis
治疗血吸虫病的临床前候选药物的鉴定
基本信息
- 批准号:9813829
- 负责人:
- 金额:$ 49.07万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-12-01 至 2021-11-30
- 项目状态:已结题
- 来源:
- 关键词:AdolescentAnimal ModelAntioxidantsBindingBinding SitesBiochemicalBiochemistryBiological AssayBiological AvailabilityCell SurvivalCellsCessation of lifeChemicalsChronic DiseaseClinicalCollaborationsComplementComplexComputer AssistedComputer-Aided DesignCountryCrystallizationDevelopmentDiagnosticDiseaseDrug TargetingDrug resistanceEnzymesEvolutionFundingGlutathione ReductaseHumanIn VitroInfectionInternationalInterruptionLibrariesLigandsLiver MicrosomesMammalian CellMediator of activation proteinMedicalMetabolicMolecularMolecular TargetMorbidity - disease rateMusOralOxadiazolesOxidation-ReductionOxidesParasite resistancePharmaceutical ChemistryPharmaceutical PreparationsPharmacologyPharmacotherapyPhasePlasmaPraziquantelPraziquantel resistancePrevalencePropertyRNA InterferenceRecombinant ProteinsResearchResistanceSchistosomaSchistosome ParasiteSchistosomiasisSelenocysteineSeminalStructureStudy modelsTXN geneToxic effectUnited States National Institutes of HealthVertebratesX-Ray Crystallographyanalogbasecandidate selectionchemoproteomicschemotherapycytotoxicitydesigndisabilitydrug candidatedrug developmentdrug discoveryenzyme activityglutaredoxinhigh throughput screeningimprovedin vivoinhibitor/antagonistinnovationiterative designlead optimizationmouse modelneglectnew therapeutic targetnext generationnovelnovel therapeuticspharmacokinetics and pharmacodynamicspre-clinicalsmall moleculesmall molecule inhibitorstructural biologythioredoxin reductasetransmission process
项目摘要
PROJECT SUMMARY/ABSTRACT
Schistosome parasites infect 200 million people, resulting in significant morbidity and more than 200,000
deaths annually. Schistosomiasis control strategies rely almost exclusively on chemotherapy and tens of
millions of people are treated with the only available drug, praziquantel (PZQ). There are no new drugs in the
clinical pipeline. PZQ cure rates obtained in mass drug administration campaigns are typically less than 50%.
Furthermore, with projected levels of PZQ use it is inevitable that PZQ-resistant parasites will evolve.
Therefore, it is imperative to identify new drug targets and drugs for schistosomiasis treatment. We identified a
highly promising drug target: the worm selenocysteine-containing enzyme thioredoxin glutathione reductase
(TGR). We established that TGR is a central and essential mediator of antioxidant defenses in the worm. The
antioxidant defenses of vertebrates are diversified to three independent enzymes, glutathione reductase,
thioredoxin reductase, and glutaredoxin, whereas schistosomes rely solely on TGR. TGR is a chokepoint and
its inhibition leads to rapid worm death in all developmental stages. In contrast, PZQ has poor activity against
juvenile worms, often resulting in partial cures. We have shown that TGR is druggable, can be selectively
targeted over human orthologous enzymes and that its inhibition in worms in an animal model of
schistosomiasis leads to worm death. PZQ analogs are inactive, restricting analog development to avoid or
counteract drug resistance. Unlike PZQ for which the mechanism of action is not known, TGR is a defined
molecular target, active as a recombinant protein, with established biochemical assays amenable to rapid
compound analysis, SAR, and optimization. We recently completed a multi-tiered HTS of a large compound
library (>350,000 compounds), which identified >100 TGR inhibitors that were inactive against off-target,
orthologous human enzymes and nontoxic to mammalian cells. The identification of these hits demonstrates
that specific inhibitors of TGR can be obtained without off-target interactions and cytotoxicity. We have
obtained both liganded and ligand-free crystal structures of TGR, allowing a structure based approach to hit
optimization. We hypothesize that iterative medicinal chemistry optimization will yield potent and selective
small molecule TGR inhibitors that will have in vivo worm killing activity. In the R21 phase our aims are to
identify hits from the multi-tiered HTS with potent (< 5 µM) worm killing activity and to characterize the TGR
binding site of these inhibitors by co-crystallization with TGR and crystal structure determination. In the R33
phase we propose to optimize these novel, potent TGR inhibitors using cutting-edge, structure and ligand-
based computer-aided design and medicinal chemistry to improve potency, stability, and oral bioavailability.
This will be complemented by X-ray crystallography and chemoproteomics using photoreactive probes to
characterize molecular TGR-compound interactions. Medicinal chemistry will be informed by enzymatic
analysis of TGR and orthologous human enzymes, metabolic stability, in vitro cell toxicity, and activity against
ex vivo worms. Finally, select compounds will be assessed for PK/PD properties and efficacy against
schistosome infections in mice. To accomplish these transformative aims, an innovative international
collaboration of global experts with expertise in schistosome biochemistry and drug discovery, structural
biology, computer-aided molecular design, and chemoproteomics has been assembled. The varied and
synergistic expertise of the team will facilitate overcoming critical barriers to drug development. Completion of
the project will identify preclinical drug-like compounds, suitable for candidate selection for schistosomiasis
treatment.
项目总结/文摘
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Pavel A Petukhov其他文献
Pavel A Petukhov的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Pavel A Petukhov', 18)}}的其他基金
Identification of the target of meclonazepam in schistosome worms
甲氯硝西泮在血吸虫中作用靶点的鉴定
- 批准号:
10218461 - 财政年份:2021
- 资助金额:
$ 49.07万 - 项目类别:
Identification of the target of meclonazepam in schistosome worms
甲氯硝西泮在血吸虫中作用靶点的鉴定
- 批准号:
10357874 - 财政年份:2021
- 资助金额:
$ 49.07万 - 项目类别:
Small Molecule Inhibitors of Malate Synthase against M. Tuberculosis
抗结核分枝杆菌的苹果酸合酶小分子抑制剂
- 批准号:
7706254 - 财政年份:2009
- 资助金额:
$ 49.07万 - 项目类别:
Small Molecule Inhibitors of Malate Synthase against M. Tuberculosis
抗结核分枝杆菌的苹果酸合酶小分子抑制剂
- 批准号:
7897873 - 财政年份:2009
- 资助金额:
$ 49.07万 - 项目类别:
Photoaffinity labeling probes for development of novel isoform selective HDAC inh
用于开发新型亚型选择性 HDAC inh 的光亲和标记探针
- 批准号:
7525598 - 财政年份:2008
- 资助金额:
$ 49.07万 - 项目类别:
Photoaffinity labeling probes for development of novel isoform selective HDAC inh
用于开发新型亚型选择性 HDAC inh 的光亲和标记探针
- 批准号:
8067976 - 财政年份:2008
- 资助金额:
$ 49.07万 - 项目类别:
Photoaffinity labeling probes for development of novel isoform selective HDAC inh
用于开发新型亚型选择性 HDAC inh 的光亲和标记探针
- 批准号:
7841892 - 财政年份:2008
- 资助金额:
$ 49.07万 - 项目类别:
Photoaffinity labeling probes for development of novel isoform selective HDAC inh
用于开发新型亚型选择性 HDAC inh 的光亲和标记探针
- 批准号:
7648175 - 财政年份:2008
- 资助金额:
$ 49.07万 - 项目类别:
Small molecule inhibitors pantothenate synthesis against M. tuberculosis
针对结核分枝杆菌的小分子泛酸合成抑制剂
- 批准号:
7243999 - 财政年份:2006
- 资助金额:
$ 49.07万 - 项目类别:
Tools for AD Research: Design of BACE2 Ligands
AD 研究工具:BACE2 配体的设计
- 批准号:
7021009 - 财政年份:2006
- 资助金额:
$ 49.07万 - 项目类别:
相似海外基金
Quantification of Neurovasculature Changes in a Post-Hemorrhagic Stroke Animal-Model
出血性中风后动物模型中神经血管变化的量化
- 批准号:
495434 - 财政年份:2023
- 资助金额:
$ 49.07万 - 项目类别:
Small animal model for evaluating the impacts of cleft lip repairing scar on craniofacial growth and development
评价唇裂修复疤痕对颅面生长发育影响的小动物模型
- 批准号:
10642519 - 财政年份:2023
- 资助金额:
$ 49.07万 - 项目类别:
Bioactive Injectable Cell Scaffold for Meniscus Injury Repair in a Large Animal Model
用于大型动物模型半月板损伤修复的生物活性可注射细胞支架
- 批准号:
10586596 - 财政年份:2023
- 资助金额:
$ 49.07万 - 项目类别:
A Comparison of Treatment Strategies for Recovery of Swallow and Swallow-Respiratory Coupling Following a Prolonged Liquid Diet in a Young Animal Model
幼年动物模型中长期流质饮食后吞咽恢复和吞咽呼吸耦合治疗策略的比较
- 批准号:
10590479 - 财政年份:2023
- 资助金额:
$ 49.07万 - 项目类别:
Diurnal grass rats as a novel animal model of seasonal affective disorder
昼夜草鼠作为季节性情感障碍的新型动物模型
- 批准号:
23K06011 - 财政年份:2023
- 资助金额:
$ 49.07万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Longitudinal Ocular Changes in Naturally Occurring Glaucoma Animal Model
自然发生的青光眼动物模型的纵向眼部变化
- 批准号:
10682117 - 财政年份:2023
- 资助金额:
$ 49.07万 - 项目类别:
A whole animal model for investigation of ingested nanoplastic mixtures and effects on genomic integrity and health
用于研究摄入的纳米塑料混合物及其对基因组完整性和健康影响的整体动物模型
- 批准号:
10708517 - 财政年份:2023
- 资助金额:
$ 49.07万 - 项目类别:
A Novel Large Animal Model for Studying the Developmental Potential and Function of LGR5 Stem Cells in Vivo and in Vitro
用于研究 LGR5 干细胞体内外发育潜力和功能的新型大型动物模型
- 批准号:
10575566 - 财政年份:2023
- 资助金额:
$ 49.07万 - 项目类别:
Elucidating the pathogenesis of a novel animal model mimicking chronic entrapment neuropathy
阐明模拟慢性卡压性神经病的新型动物模型的发病机制
- 批准号:
23K15696 - 财政年份:2023
- 资助金额:
$ 49.07万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
The effect of anti-oxidant on swallowing function in an animal model of dysphagia
抗氧化剂对吞咽困难动物模型吞咽功能的影响
- 批准号:
23K15867 - 财政年份:2023
- 资助金额:
$ 49.07万 - 项目类别:
Grant-in-Aid for Early-Career Scientists