Discovery of Antimalarials with Novel Mechanism of Action
Discovery of Antimalarials with Novel Mechanism of Action
批准号:
10320854
负责人:
DEBOPAM CHAKRABARTI
金额:
$37.04万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-01-01 至 2023-12-31
关键词:
AntimalarialsAppearanceAreaArtemisininsBiological PharmacologyBloodCellsCessation of lifeChemicalsChildCollectionDataDevelopmentDiseaseDrug KineticsDrug resistanceEconomicsEffectivenessErythrocytesExhibitsFalciparum MalariaFloridaIn VitroIndividualInterventionLaboratoriesLeadLibrariesLife Cycle StagesMalariaMammalian CellMeasuresModelingMolecular TargetMulti-Drug ResistanceMusMyanmarNatural ProductsParasite resistanceParasitesPersonsPharmaceutical PreparationsPharmacologyPharmacology and ToxicologyPlayPopulationPrevalencePropertyProteomicsPublishingResearchResistanceResistance developmentResistance profileResourcesRodentRodent ModelRoleSoutheastern AsiaSpeedStructureTestingTherapeuticTimeToxicologyUniversitiesVietnamanalogasexualbasecellular targetingcheminformaticsdesignefficacy evaluationexperiencegenome sequencingglobal healthimprovedin vivoin vivo evaluationlead optimizationnanomolarnext generationnovelnovel therapeuticsresistance mechanismscaffoldsmall moleculetransmission processwhole genome
中文摘要
疟疾仍然困扰着世界上大约一半的人口,导致大约50万人死亡,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
由于广泛出现的疟疾,用于治疗疟疾的药物正在失去效力
抗药性。即使是以青蒿素为基础的联合治疗(ACT)也是一线
在疟疾流行地区,治疗恶性疟疾的方法显示出抗药性的迹象。
东南亚。因此,迫切需要寻找作用于新靶点的新的药物先导。
开发下一代治疗疟疾的方法。我们已经筛选了
化学信息学-从生物设计库中挑选出2,115个独特的支架,该库整合了
用于抗疟原虫活动的药理上相关的天然产品的特权特征。
这个筛查已经确定了两种支架,它们表现出强大的抗疟原虫活性,作用时间较早
寄生虫的无性生命周期,包括入侵。其中一个脚手架也具有阶段V
配子体活动。拟议的研究旨在建立和进一步发展这些小说
抗疟疾的化学类型。我们假设这些化学类型将是用于
将产生有效的抗疟疾先导化合物靶向的点击到领先的优化研究
与目前的疟疾药物不同的细胞机制。实现……的目标
为了开发新的疟疾疗法并证明我们的假设,我们计划:(A)设计和
利用结构-活性和结构-性质合成早效先导化合物
关系研究。(B)确定特定阶段的作用、抗药性概况、药理学
性质、体内药代动力学、毒理学、传播阻断活性和抗疟疾
功效。(C)通过全基因组测序确定支架的分子靶点
抗性品系和化学蛋白质组学。拟议的研究具有重要意义,因为在
该项目结束时,我们希望有新的抗疟疾先导化合物与明确
作用机制。
英文摘要
Malaria still afflicts about half of the world population causing about 500,000 deaths, mostly
children. The global economic toll of malaria is enormous. Most of the drugs that are currently
utilized for malaria treatment are losing their effectiveness due to widespread emergence of
drug resistance. Even artemisinin-based combination treatments (ACTs) that are the front-line
therapies against falciparum malaria are showing signs of resistance in endemic regions of
Southeast Asia. Therefore, it is urgent to identify new drug leads acting on novel targets for the
development of next generation of therapies against malaria. We have screened
cheminformatics-selected 2,115 unique scaffolds from a BioDesign library that incorporates
privileged features of pharmacologically relevant natural products for antiplasmodial activities.
This screen has identified two scaffolds that exhibit potent antiplasmodial activity, acting early
on parasite's asexual life cycle, including invasion. One of the scaffold also possess stage V
gametocyte activity. The proposed research seeks to establish and further develop these novel
antimalarial chemotypes. We hypothesize that these chemotypes will be excellent platforms for
hit-to-lead optimization studies that will yield effective antimalarial lead compounds targeting
cellular mechanisms distinct from current malaria drugs. To accomplish the objective of
developing new malaria therapeutics and prove our hypothesis, we plan to: (a) Design and
synthesize early-acting lead compounds through structure-activity and structure-property
relationship studies. (b) Determine stage-specific action, resistance profile, pharmacological
properties, in vivo pharmacokinetics, toxicology, transmission blocking activity, and antimalarial
efficacy. (c) Determine molecular targets of the scaffolds by whole genome sequencing of
resistant lines and chemical proteomics. The proposed research is highly significant because at
the end of the project we expect to have novel antimalarial lead compounds with defined
mechanism of action.
期刊论文(3)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1021/acs.jmedchem.0c00858
发表时间:
2020-10-22
期刊:
Journal of medicinal chemistry
影响因子:
7.3
作者:
[Huang G, Murillo Solano C, Melendez J, Shaw J, Collins J, Banks R, Arshadi AK, Boonhok R, Min H, Miao J, Chakrabarti D, Yuan Y]
通讯作者:
Yuan Y
Discovery of fast-acting dual-stage antimalarial agents by profiling pyridylvinylquinoline chemical space via copper catalyzed azide-alkyne cycloadditions.
通过通过铜叠叠叠式叠氮化物环载体来分析吡啶基乙烯基素氨酸化学空间,从而发现快速作用的双阶段抗疟药剂。
DOI:
10.1016/j.ejmech.2020.112889
发表时间:
2021-01-01
期刊:
European journal of medicinal chemistry
影响因子:
6.7
作者:
[Huang G, Solano CM, Melendez J, Yu-Alfonzo S, Boonhok R, Min H, Miao J, Chakrabarti D, Yuan Y]
通讯作者:
Yuan Y
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:
Novel Antimalarials from Fungi
-
批准号:10388240
-
项目类别:
-
资助金额:$75.69万
-
财政年份:2020
-
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
-
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
-
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