Preclinical optimization of a parasiticidal drug for cryptosporidiosis
隐孢子虫病杀寄生虫药物的临床前优化
基本信息
- 批准号:10569660
- 负责人:
- 金额:$ 69.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-03-01 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:ADME StudyAccelerationAcquired Immunodeficiency SyndromeAddressAdultAffectAnimalsAntiparasitic AgentsArrhythmiaBiliaryBiochemicalBiological AssayBiologyBloodCRISPR/Cas technologyCardiotoxicityCharacteristicsChildChronicClinicalCryptosporidiosisCryptosporidiumCryptosporidium parvumCytochrome P450DairyingDiarrheaDisease OutbreaksDissectionDoseDrug DesignDrug InteractionsDrug TargetingDrug resistanceEnzymesEthersEuropeExcretory functionExposure toFutureGenesGeneticGnotobioticGoalsHumanImmunocompromised HostIn VitroInfantInfectionIntestinesLeadLifeMalariaMethodsModelingMolecular Mechanisms of ActionMolecular TargetMusMutationOralOutcomeParasitesPatientsPeriodicityPharmaceutical ChemistryPharmaceutical PreparationsPharmacologyPhenotypePiperazinesPlacebosPlasmodiumPotassium ChannelPropertyProteinsPublic HealthResearchResistanceResourcesSafetySeriesSmall IntestinesStructureTestingTissuesToxic effectToxicologyTransplant RecipientsUnited StatesValidationWorkanalogchemical synthesischemoproteomicsclinical candidateclinical developmentclinical efficacydiarrheal diseasedrug candidatedrug developmentdrug discoveryenteric infectiongenome sequencingimprovedin vitro Assayin vivointestinal epitheliumlead optimizationmanufacturing costmouse modelnitazoxanidenovelpatient populationpharmacokinetics and pharmacodynamicsporcine modelpre-clinicalprogramsresistant Plasmodium falciparumscreeningsuccesswaterbornewhole genome
项目摘要
PROJECT SUMMARY
Cryptosporidiosis is amongst the most important causes of life-threatening diarrhea in children globally, causes
incurable diarrhea in AIDS and transplant patients, and is the most common cause of waterborne diarrheal
outbreaks in the United States. Almost all human cases of cryptosporidiosis are due to infection of the small
intestinal epithelium with one of two species of Cryptosporidium parasites, C. parvum or C. hominis.
Nitazoxanide, the only approved drug, is efficacious in otherwise healthy adults, but unfortunately, has limited
efficacy (~56%) in children and is equivalent to a placebo in AIDS patients. The long-term goal of this research
program is to develop improved drugs to treat cryptosporidiosis. In this project, a parasiticidal piperazine-
based lead compound with extraordinary in vivo efficacy that was identified by phenotypic screening will be
optimized, and its molecular mechanism of action will be determined. The lead optimization program is guided
by an ideal target product profile and milestones to provide a pre-clinical lead that is likely to be effective in all
patient populations affected by Cryptosporidium and has safety characteristics suitable for treatment of infants,
minimal drug-drug interactions, minimal oral dosing requirements, stability in the tropics, and a low
manufacturing cost. The methods for lead optimization bring together novel in vitro assays and a highly
immunocompromised mouse model of cryptosporidiosis with well-established pharmacology and medicinal
chemistry approaches. For this, cyclic rounds of chemical synthesis will be combined with in vitro
Cryptosporidium assays, in vitro ADME studies, mouse PK studies, and a chronic mouse model of C. parvum
infection. A piglet model will then be used to test clinical efficacy against C. hominis. The method for drug
target identification will take advantage of the lead compound's activity against related malaria parasites to
identify mutations associated with drug resistance and candidate drug targets, followed by CRISPR/Cas9
validation of mutations in C. parvum and biochemical methods to assess direct protein-drug interactions.
Success would yield an optimized clinical candidate that is ready to be advanced to testing in regulatory
toxicology studies, and a validated drug target that will accelerate drug development by enabling target-based
drug design and target-based screening efforts to identify additional chemotypes. Given the dire need for new
cryptosporidiosis drugs, the public health impact of success could be extremely significant.
项目总结
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Structure-Activity relationships of replacements for the triazolopyridazine of Anti-Cryptosporidium lead SLU-2633.
抗隐孢子虫先导物 SLU-2633 的三唑并哒嗪替代物的构效关系。
- DOI:10.1016/j.bmc.2023.117295
- 发表时间:2023
- 期刊:
- 影响因子:3.5
- 作者:Oboh,Edmund;Teixeira,JoséE;Schubert,TannerJ;Maribona,AdrianaS;Denman,BrylonN;Patel,Radhika;Huston,ChristopherD;Meyers,MarvinJ
- 通讯作者:Meyers,MarvinJ
Structure-Activity Relationship Studies of the Aryl Acetamide Triazolopyridazines against Cryptosporidium Reveals Remarkable Role of Fluorine.
芳基乙酰胺三唑并哒嗪抗隐孢子虫的构效关系研究揭示了氟的显着作用。
- DOI:10.1021/acs.jmedchem.3c00110
- 发表时间:2023
- 期刊:
- 影响因子:7.3
- 作者:Schubert,TannerJ;Oboh,Edmund;Peek,Hannah;Philo,Emily;Teixeira,JoséE;Stebbins,ErinE;Miller,Peter;Oliva,Jonathan;Sverdrup,FrancisM;Griggs,DavidW;Huston,ChristopherD;Meyers,MarvinJ
- 通讯作者:Meyers,MarvinJ
Optimization of the Urea Linker of Triazolopyridazine MMV665917 Results in a New Anticryptosporidial Lead with Improved Potency and Predicted hERG Safety Margin.
- DOI:10.1021/acs.jmedchem.1c01136
- 发表时间:2021-08-12
- 期刊:
- 影响因子:7.3
- 作者:Oboh E;Schubert TJ;Teixeira JE;Stebbins EE;Miller P;Philo E;Thakellapalli H;Campbell SD;Griggs DW;Huston CD;Meyers MJ
- 通讯作者:Meyers MJ
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CHRISTOPHER D HUSTON其他文献
CHRISTOPHER D HUSTON的其他文献
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{{ truncateString('CHRISTOPHER D HUSTON', 18)}}的其他基金
Methods to study Cryptosporidium drug resistance
研究隐孢子虫耐药性的方法
- 批准号:
10591168 - 财政年份:2022
- 资助金额:
$ 69.98万 - 项目类别:
Repurposing the EMD-Serono "mini-library" for Cryptosporidium drug development
重新利用 EMD-Serono“迷你库”进行隐孢子虫药物开发
- 批准号:
10320256 - 财政年份:2019
- 资助金额:
$ 69.98万 - 项目类别:
Preclinical optimization of a parasiticidal drug for cryptosporidiosis
隐孢子虫病杀寄生虫药物的临床前优化
- 批准号:
10356051 - 财政年份:2019
- 资助金额:
$ 69.98万 - 项目类别:
Repurposing the EMD-Serono "mini-library" for Cryptosporidium drug development
重新利用 EMD-Serono“迷你库”进行隐孢子虫药物开发
- 批准号:
10548847 - 财政年份:2019
- 资助金额:
$ 69.98万 - 项目类别:
Novel approaches to develop a treatment for cryptosporidiosis
开发隐孢子虫病治疗方法的新方法
- 批准号:
8605836 - 财政年份:2013
- 资助金额:
$ 69.98万 - 项目类别:
Novel approaches to develop a treatment for cryptosporidiosis
开发隐孢子虫病治疗方法的新方法
- 批准号:
8511900 - 财政年份:2013
- 资助金额:
$ 69.98万 - 项目类别:
VERMONT COBRE: PROJECT 3: MECHANISM OF ENTAMOEBA HISTOLYTICA PHAGOCYTOSIS
佛蒙特州 COBRE:项目 3:溶组织内阿米巴吞噬机制
- 批准号:
8360773 - 财政年份:2011
- 资助金额:
$ 69.98万 - 项目类别:
VERMONT COBRE: PROJECT 3: MECHANISM OF ENTAMOEBA HISTOLYTICA PHAGOCYTOSIS
佛蒙特州 COBRE:项目 3:溶组织内阿米巴吞噬机制
- 批准号:
8167732 - 财政年份:2010
- 资助金额:
$ 69.98万 - 项目类别:
VERMONT COBRE: PROJECT 3: MECHANISM OF ENTAMOEBA HISTOLYTICA PHAGOCYTOSIS
佛蒙特州 COBRE:项目 3:溶组织内阿米巴吞噬机制
- 批准号:
7959818 - 财政年份:2009
- 资助金额:
$ 69.98万 - 项目类别:
Molecular Mechanism of Entamoeba histolytica phagocytosis
溶组织内阿米巴吞噬作用的分子机制
- 批准号:
7916951 - 财政年份:2009
- 资助金额:
$ 69.98万 - 项目类别:
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