ASSESSING IN VITRO/VIVO EFFICACY OF ANTIMALARIAL ENR INHIBITORS
评估抗疟 ENR 抑制剂的体外/体内功效
基本信息
- 批准号:7631383
- 负责人:
- 金额:$ 24.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:4-aminoquinolineAIDS/HIV problemAcetatesActive SitesAntimalarialsBindingBioavailableBiochemistryCause of DeathChemical StructureChemicalsChemistryChloroquineChloroquine resistanceCommunicable DiseasesComplementCritical PathwaysDevelopmentDiseaseDrug Delivery SystemsDrug Metabolic DetoxicationDrug resistanceDrug-sensitiveEnzymesEthionamideFalciparum MalariaFatty AcidsFolate Biosynthesis PathwayFolic Acid AntagonistsGoalsHealthHemeHousehold ProductsHumanIn VitroInfectionInfectious AgentInterdisciplinary StudyInvestigationKnowledgeMalariaMeasuresMedicineModelingMolecular BiologyOxidoreductaseParasitesParasitologyPathway interactionsPharmaceutical PreparationsPharmacologic SubstancePlasmodiumPlasmodium falciparumPrincipal InvestigatorPropertyPyrimethamine-SulfadoxineReagentReportingResearchResistanceResourcesRodentSeriesSpecificitySystemTestingTexasTransgenic OrganismsTriclosanTuberculosisUniversitiesWorkadductantimicrobial drugbasecollegedesignhigh throughput screeningin vivoinhibitor/antagonistinterdisciplinary approachisoniazidkillingsnovelpre-clinicalprogramsstructural biologytissue/cell culturetool
项目摘要
Malaria caused by infection with Plasmodium falciparum exerts an enormous toll on human health in tropical regions. Current antimalarial treatments are being severely compromised by the spread of P. falciparum strains resistant to chloroquine (that interferes with heme detoxification) and pyrimethamine-sulfadoxine (that inhibits folate biosynthesis). Several groups have recently defmed P. falciparum type II fatty acid synthesis (FAS-II), an apicoplast pathway that is lacking in humans, as a unique drug target. The FAS-II enzyme enoyl ACP reductase (ENR) is the target of several widely used antimicrobial agents including triclosan, isoniazid and ethionamide. Our Program, representing a public/private partnership between GlaxoSmithKline, Texas A&M University and the Albert Einstein College of Medicine, proposes to implement a high throughput screen against purified P. falciparum ENR (PfENR) and follow this with a Hits to Leads program that integrates chemistry, biochemistry, structural biology, molecular biology and parasitology. In Aim 1 of this project, we will evaluate the efficacy of test ENR inhibitors against drug-resistant
and drug-sensitive P. falciparum in vitro. Aim 2 will assess the in vivo efficacy of promising
PfENR inhibitors, using non-transformed P. berghei as well as transgenic P. berghei clones expressing the enoyl ACP reductase from P. falciparum or P. vivax (the second most important human malaria species) in the place of the rodent malarial enzyme (the transgenic P. berghei lines will be generated as part of Project 3). Aim 3 proposes to develop transgenic, "mode of action" P. falciparum lines that underexpress PfENR or are functionally complemented for ENR activity, to assess inhibitor specificity. Aim 4 will develop a transgenic P. falciparum line expressing the P. vivax enr in the place of pfenr, as a surrogate model to measure in vitro activity against P. vivax. This project provides key resources and reagents to identify
potent, orally bioavailable inhibitors that can move down the critical path and enter preclinical development as new candidate antimalarial drugs.
在热带地区,由恶性疟原虫感染引起的疟疾对人类健康造成了巨大的损失。目前的抗疟治疗正受到恶性疟原虫菌株的传播的严重影响,这些菌株对氯喹(干扰血红素解毒)和乙胺嘧啶-磺胺嘧啶(抑制叶酸生物合成)具有抗药性。几个研究小组最近将恶性疟原虫II型脂肪酸合成(FAS-II)(一种人类缺乏的顶质体途径)定义为独特的药物靶点。FAS-II酶烯酰ACP还原酶(ENR)是几种广泛使用的抗菌剂(包括三氯生、异烟肼和乙硫异烟胺)的靶标。我们的计划代表葛兰素史克,德克萨斯A&M大学和阿尔伯特爱因斯坦医学院之间的公共/私人合作伙伴关系,建议对纯化的恶性疟原虫ENR(PfENR)进行高通量筛选,并随后进行整合化学,生物化学,结构生物学,分子生物学和寄生虫学的Hits to Leads计划。在本项目的目标1中,我们将评估测试ENR抑制剂对耐药细胞的有效性。
和药物敏感的恶性疟原虫。目的2将评估有前途的
PfENR抑制剂,使用非转化伯氏疟原虫以及表达来自恶性疟原虫或间日疟原虫(第二重要的人类疟疾物种)的烯酰ACP还原酶的转基因伯氏疟原虫克隆代替啮齿动物疟疾酶(转基因伯氏疟原虫系将作为项目3的一部分产生)。目的3提出开发低表达PfENR或ENR活性功能互补的转基因“作用模式”恶性疟原虫系,以评估抑制剂特异性。目的4建立间日疟原虫enr基因替代pfenr基因的恶性疟原虫转基因株系,作为测定间日疟原虫体外抗疟活性的替代模型。该项目提供了关键的资源和试剂,
有效的口服生物可利用的抑制剂,可以沿着关键路径进入临床前开发,作为新的候选抗疟疾药物。
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)
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David A Fidock其他文献
Causal chemoprophylactic activity of cabamiquine against emPlasmodium falciparum/em in a controlled human malaria infection: a randomised, double-blind, placebo-controlled study in the Netherlands
卡巴醌在受控人类疟疾感染中对恶性疟原虫的因果化学预防活性:荷兰的一项随机、双盲、安慰剂对照研究
- DOI:
10.1016/s1473-3099(23)00212-8 - 发表时间:
2023-10-01 - 期刊:
- 影响因子:31.000
- 作者:
Johan L van der Plas;Vincent P Kuiper;Wilhelmina M Bagchus;Matthias Bödding;Özkan Yalkinoglu;Aliona Tappert;Andrea Seitzinger;Thomas Spangenberg;Deon Bezuidenhout;Justin Wilkins;Claude Oeuvray;Satish K Dhingra;Vandana Thathy;David A Fidock;Lisanne C A Smidt;Geert V T Roozen;Jan Pieter R Koopman;Olivia A C Lamers;Jeroen Sijtsma;Roos van Schuijlenburg;Akash Khandelwal - 通讯作者:
Akash Khandelwal
Safety, tolerability, pharmacokinetics, and antimalarial activity of MMV533: a phase 1a first-in-human, randomised, ascending dose and food effect study, and a phase 1b emPlasmodium falciparum/em volunteer infection study
MMV533 的安全性、耐受性、药代动力学和抗疟活性:一项 1a 期首次人体、随机、递增剂量和食物效应研究,以及一项 1b 期恶性疟原虫/志愿者感染研究
- DOI:
10.1016/s1473-3099(24)00664-9 - 发表时间:
2025-05-01 - 期刊:
- 影响因子:31.000
- 作者:
Benoit Bestgen;Sam Jones;Vandana Thathy;Andrea Kuemmerle;Catalina Barcelo;Amina Haouala;Denis Gossen;Michael W Marx;Ilaria Di Resta;Maja Szramowska;Rebecca A Webster;Stacey Llewellyn;Dominic A Ritacco;Tomas Yeo;Didier Leroy;Bridget E Barber;David A Fidock;Paul Griffin;Jason Lickliter;Stephan Chalon - 通讯作者:
Stephan Chalon
emPlasmodium falciparum/em resistance to artemisinin-based combination therapies
- DOI:
10.1016/j.mib.2022.102193 - 发表时间:
2022-10-01 - 期刊:
- 影响因子:7.500
- 作者:
Kurt E Ward;David A Fidock;Jessica L Bridgford - 通讯作者:
Jessica L Bridgford
Regional action needed to halt antimalarial drug resistance in Africa
需要采取区域行动来阻止非洲的抗疟药物耐药性。
- DOI:
10.1016/s0140-6736(24)02706-5 - 发表时间:
2025-01-04 - 期刊:
- 影响因子:88.500
- 作者:
Rosario Martinez-Vega;Deus S Ishengoma;Roly Gosling;Philip J Rosenthal;Arjen Dondorp;Karen I Barnes;Christian Nsanzabana;Abdoulaye A Djimde;Lynette I Ochola-Oyier;James Tibenderana;John Chimumbwa;Lemu Golassa;Ntuli A Kapologwe;Wilfred F Mbacham;Moses R Kamya;David A Fidock;Ryuichi Komatsu;Lorenz von Seidlein;Mehul Dhorda - 通讯作者:
Mehul Dhorda
David A Fidock的其他文献
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{{ truncateString('David A Fidock', 18)}}的其他基金
Deciphering the role of Plasmodium falciparum plasmepsin 2/3 amplifications in mutant pfcrt-driven piperaquine resistance
破译恶性疟原虫血浆蛋白酶 2/3 扩增在突变体 pfcrt 驱动的哌喹耐药中的作用
- 批准号:
10374934 - 财政年份:2021
- 资助金额:
$ 24.8万 - 项目类别:
Leveraging PfCRT Structure to Discern Function and Predict Emergence of Drug-Resistant Malaria
利用 PfCRT 结构识别功能并预测耐药性疟疾的出现
- 批准号:
10443625 - 财政年份:2019
- 资助金额:
$ 24.8万 - 项目类别:
Leveraging PfCRT Structure to Discern Function and Predict Emergence of Drug-Resistant Malaria
利用 PfCRT 结构识别功能并预测耐药性疟疾的出现
- 批准号:
10199925 - 财政年份:2019
- 资助金额:
$ 24.8万 - 项目类别:
Leveraging PfCRT Structure to Discern Function and Predict Emergence of Drug-Resistant Malaria
利用 PfCRT 结构识别功能并预测耐药性疟疾的出现
- 批准号:
10653063 - 财政年份:2019
- 资助金额:
$ 24.8万 - 项目类别:
Elucidating the molecular basis of piperaquine resistance in Plasmodium falciparum
阐明恶性疟原虫哌喹耐药的分子基础
- 批准号:
10595160 - 财政年份:2016
- 资助金额:
$ 24.8万 - 项目类别:
Elucidating the molecular basis of piperaquine resistance and the role of altered hemoglobin metabolism in Plasmodium falciparum
阐明恶性疟原虫哌喹耐药性的分子基础以及血红蛋白代谢改变的作用
- 批准号:
9212775 - 财政年份:2016
- 资助金额:
$ 24.8万 - 项目类别:
Elucidating the molecular basis of piperaquine resistance and the role of altered hemoglobin metabolism in Plasmodium falciparum
阐明恶性疟原虫哌喹耐药性的分子基础以及血红蛋白代谢改变的作用
- 批准号:
9127601 - 财政年份:2016
- 资助金额:
$ 24.8万 - 项目类别:
Defining P. falciparum resistance to artemisinin-based combination therapies
恶性疟原虫对青蒿素联合疗法的耐药性的定义
- 批准号:
9319626 - 财政年份:2014
- 资助金额:
$ 24.8万 - 项目类别:
Defining P. falciparum resistance to artemisinin-based combination therapies
恶性疟原虫对青蒿素联合疗法的耐药性的定义
- 批准号:
8788180 - 财政年份:2014
- 资助金额:
$ 24.8万 - 项目类别:
Columbia University Graduate Training Program in Microbiology and Immunology
哥伦比亚大学微生物学和免疫学研究生培训项目
- 批准号:
8742419 - 财政年份:2014
- 资助金额:
$ 24.8万 - 项目类别: