Novel Antimalarials from Fungi
Novel Antimalarials from Fungi
批准号:
10388240
负责人:
DEBOPAM CHAKRABARTI
金额:
$75.69万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-05-18 至 2025-04-30
关键词:
AddressAnti-Infective AgentsAntimalarialsAppearanceAreaArtemisininsBioinformaticsBiologicalCRISPR/Cas technologyCaliforniaCellular biologyCessation of lifeChemicalsChildChildhoodClinicalCopy Number PolymorphismCountryDataDevelopmentDiseaseDrug KineticsDrug resistanceEconomicsEffectivenessEvolutionFloridaGrowthHigh Pressure Liquid ChromatographyIn VitroIndividualInterdisciplinary StudyLaboratoriesLeadLibrariesLiverMalariaMeasuresMediatingMethodsModelingMoldsMolecular TargetMulti-Drug ResistanceMusMutationMyanmarNMR SpectroscopyNatural ProductsNatural Products ChemistryNatural SelectionsNatureOklahomaParasite resistanceParasitesPersonsPharmaceutical PreparationsPharmacologyPhenotypePopulationPrevalencePropertyProteinsProteomeResearchResistanceResistance profileResolutionResource DevelopmentResourcesSourceSoutheastern AsiaSpecimenSpectrometry, Mass, Electrospray IonizationStructureTexasTherapeuticTimeUniversitiesUrsidae FamilyValidationVietnambasecellular targetingcomparativedrug discoveryefficacy evaluationefficacy studyexperiencefungusgenome editinggenome sequencingglobal healthimprovedin vivoin vivo evaluationmacromoleculemortalitynext generationnovelnovel lead compoundnovel therapeuticspharmacophoreresistant strainscaffoldscreeningsmall molecule therapeuticstargeted treatmentwhole genome
中文摘要
疟疾仍然困扰着世界上大约一半的人口,导致40多万人死亡,其中大部分
孩子们。疟疾在全球造成的经济损失是巨大的。目前使用的大多数药物
用于疟疾治疗,包括以青蒿素为基础的联合治疗正在失败
它们的有效性归功于广泛出现的耐药性。要解决脆弱的问题
在疟疾治疗方面,我们建议通过筛选一种新的抗疟疾化合物
真菌次生代谢物库。我们假设真菌次生代谢物,
对于抗疟疾发现的探索不足,将为我们提供一个独特的机会
调查与医学相关但尚未开发的化学空间,以发现新的疟疾
治疗学。此提案的前提是基于我们前景看好的初步筛选,该筛选具有
鉴定真菌提取物和真菌来源的纯化合物,具有强大的抗疟原虫活性。
为了证明这一假设,我们在这里建议(1)筛选一个由10,000个提取物组成的文库
从不同的真菌物种和取消复制优先生物活性提取物,以识别和
确定选择性抗疟原虫化合物的结构,这些化合物对多种
寄生虫的发育阶段;将对命中率进行筛选,以确定交叉耐药性和杀伤力
费率。(2)体外物理化学、体内药理学将优先考虑活性物质
和体内疗效研究。(3)优先命中的目标标识将由In确定
抗性的体外进化和全基因组测序。目标验证将是
由CRISPR/Cas9介导的基因组编辑进行。这项工作的研究将是
通过Debopam实验室之间的多学科合作进行
查克拉巴蒂(中佛罗里达大学)、罗伯特·奇切维茨(俄克拉荷马大学)、柯尔斯滕
汉森(德克萨斯大学圣安东尼奥分校),伊丽莎白·温泽勒和耶利米·蒙珀
(加州大学圣地亚哥分校)拥有天然产品化学的综合专业知识,
疟疾细胞生物学、抗感染药物发现、目标识别和验证。这是一个高度的
重大的努力,因为我们将发现新的先导化合物,具有有效的目标
治疗耐多药疟疾。
英文摘要
Malaria still afflicts about half of the world population causing more than 400,000 deaths, mostly
children. The global economic toll of malaria is enormous. Most of the drugs that are currently
utilized for malaria treatment, including artemisinin-based combination treatments are losing
their effectiveness due to widespread emergence of drug resistance. To address the fragility of
malaria therapy, we propose to discover novel antimalarial compounds through screening of a
library of fungal secondary metabolites. We hypothesize that fungal secondary metabolites, which
are underexplored for antimalarial discovery, will provide us with a unique opportunity to
investigate medicinally relevant but untapped chemical space for the discovery of novel malaria
therapeutics. Premise for this proposal is based on our promising preliminary screen that has
identified fungal extracts and pure compounds of fungal origin with potent antiplasmodial activities.
To prove this hypothesis, we propose herein to (1) Screen a library of 10,000 extracts derived
from diverse fungal species and dereplicate prioritized bioactive extracts to identify and
determine structures of selective antiplasmodial compounds that are active against multiple
parasite developmental stages; hits will be screened to determine cross-resistance, and killing
rate. (2) Active compounds will be prioritized by in vitro physicochemical, in vivo pharmacology
and in vivo efficacy studies. (3) Target identification of prioritized hits will be determined by in
vitro evolution of resistance followed by whole genome sequencing. Target validation will be
conducted by CRISPR/Cas9 mediated genome editing. The research in this endeavor will be
conducted through a multidisciplinary collaboration between the laboratories of Debopam
Chakrabarti (University of Central Florida), Robert Cichewicz (University of Oklahoma), Kirsten
Hanson (University of Texas San Antonio), Elizabeth Winzeler and Jeremiah Momper
(University of California San Diego) with combined expertise in natural product chemistry,
malaria cell biology, anti-infective discovery, target identification, and validation. This is a highly
significant endeavor, as we will discover novel lead compounds with validated targets for
therapy against multidrug resistant malaria.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Plasmodium Protein Kinase Focused Antimalarials Discovery
-
批准号:10533634
-
项目类别:
-
资助金额:$80.13万
-
财政年份:2022
-
负责人:DEBOPAM CHAKRABARTI
-
依托单位:
Plasmodium Protein Kinase Focused Antimalarials Discovery
-
批准号:10663334
-
项目类别:
-
资助金额:$76.9万
-
财政年份:2022
-
负责人:DEBOPAM CHAKRABARTI
-
依托单位:
Novel Antimalarials from Fungi
-
批准号:10614534
-
项目类别:
-
资助金额:$75.59万
-
财政年份:2020
-
负责人:DEBOPAM CHAKRABARTI
-
依托单位:
Novel Antimalarials from Fungi
-
批准号:10166769
-
项目类别:
-
资助金额:$75.82万
-
财政年份:2020
-
负责人:DEBOPAM CHAKRABARTI
-
依托单位:
Discovery of Antimalarials with Novel Mechanism of Action
-
批准号:10320854
-
项目类别:
-
资助金额:$37.04万
-
财政年份:2018
-
负责人:DEBOPAM CHAKRABARTI
-
依托单位:
Natural Product-Inspired Novel Synthetic Antiplasmodial Scaffolds
-
批准号:8872417
-
项目类别:
-
资助金额:$7.22万
-
财政年份:2015
-
负责人:DEBOPAM CHAKRABARTI
-
依托单位:
Novel Antimalarials from Marine Microbial Natural Products
-
批准号:8302637
-
项目类别:
-
资助金额:$22.84万
-
财政年份:2012
-
负责人:DEBOPAM CHAKRABARTI
-
依托单位:
Novel Antimalarials from Marine Microbial Natural Products
-
批准号:8424201
-
项目类别:
-
资助金额:$18.09万
-
财政年份:2012
-
负责人:DEBOPAM CHAKRABARTI
-
依托单位:
Chemical Genetics of Plasmodium Kinases
-
批准号:7879102
-
项目类别:
-
资助金额:$0.7万
-
财政年份:2009
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负责人:DEBOPAM CHAKRABARTI
-
依托单位:
Marine Natural Products as Antimalarials
-
批准号:7589385
-
项目类别:
-
资助金额:$19.05万
-
财政年份:2009
-
负责人:DEBOPAM CHAKRABARTI
-
依托单位:
Marine Natural Products as Antimalarials
-
批准号:7762252
-
项目类别:
-
资助金额:$21.35万
-
财政年份:2009
-
负责人:DEBOPAM CHAKRABARTI
-
依托单位:
Chemical Genetics of Plasmodium Kinases
-
批准号:7922270
-
项目类别:
-
资助金额:$5.4万
-
财政年份:2009
-
负责人:DEBOPAM CHAKRABARTI
-
依托单位:
Marine Natural Products as Antimalarials
-
批准号:7879131
-
项目类别:
-
资助金额:$0.7万
-
财政年份:2009
-
负责人:DEBOPAM CHAKRABARTI
-
依托单位:
Chemical Genetics of Plasmodium Kinases
-
批准号:7880575
-
项目类别:
-
资助金额:$35.26万
-
财政年份:2008
-
负责人:DEBOPAM CHAKRABARTI
-
依托单位:
Chemical Genetics of Plasmodium Kinases
-
批准号:7528116
-
项目类别:
-
资助金额:$36.67万
-
财政年份:2008
-
负责人:DEBOPAM CHAKRABARTI
-
依托单位:
Chemical Genetics of Plasmodium Kinases
-
批准号:7645600
-
项目类别:
-
资助金额:$35.62万
-
财政年份:2008
-
负责人:DEBOPAM CHAKRABARTI
-
依托单位:
CELL CYCLE OF PLASMODIUM FALCIPARUM
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批准号:6190139
-
项目类别:
-
资助金额:$24.94万
-
财政年份:2000
-
负责人:DEBOPAM CHAKRABARTI
-
依托单位:
CELL CYCLE OF PLASMODIUM FALCIPARUM
-
批准号:6374601
-
项目类别:
-
资助金额:$24.94万
-
财政年份:2000
-
负责人:DEBOPAM CHAKRABARTI
-
依托单位:
CELL CYCLE OF PLASMODIUM FALCIPARUM
-
批准号:6632420
-
项目类别:
-
资助金额:$24.94万
-
财政年份:2000
-
负责人:DEBOPAM CHAKRABARTI
-
依托单位:
CELL CYCLE OF PLASMODIUM FALCIPARUM
-
批准号:6511501
-
项目类别:
-
资助金额:$24.94万
-
财政年份:2000
-
负责人:DEBOPAM CHAKRABARTI
-
依托单位:
海外基金