Hit-to-Lead Development of the Kalihinol Scaffold for Malaria Treatment
Hit-to-Lead Development of the Kalihinol Scaffold for Malaria Treatment
批准号:
9789813
负责人:
CHOUKRI BEN MAMOUN
金额:
$72.06万
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:
2018-09-21 至 2023-08-31
关键词:
AddressAfricaAntimalarialsArtemisininsBiologicalBiological AvailabilityBiologyBloodCessation of lifeChemicalsClinicalCombined Modality TherapyCountryCulicidaeDataDevelopmentDoseDrug KineticsDrug effect disorderDrug resistanceDrug usageDrug-sensitiveErythrocytesFamilyGenomic approachGoalsGrowthHandHealthHumanIn VitroIndividualInfectionLaboratoriesLeadLearningLife Cycle StagesMED6 geneMalariaMetabolicMetabolismMusNatural ProductsParasite resistanceParasitesPathway interactionsPharmaceutical PreparationsPharmacologyPlasmodiumPlasmodium falciparumPlasmodium vivaxPropertyProphylactic treatmentPublicationsRattusRecrudescencesReportingResearchResistanceRouteSafetySamplingSolubilityStructure-Activity RelationshipTherapeutic IndexTranslatingTreatment CostVaccinesWorkanalogbasechemical synthesisclinical candidatecombatcourse developmentdesigndrug candidateefficacy studyfunctional groupglobal healthimprovedin vivoinhibitor/antagonistmalaria infectionmembermortalitymultidisciplinarynanomolarnext generationnovelnovel therapeuticspre-clinicalpreclinical developmentpreventprogramsresistance mechanismresistant Plasmodium falciparumsafety studyscaffoldscreeningtransmission processvector
中文摘要
项目概要
用于疟疾治疗的 Kalihinol 支架的 Hit-to-Lead 开发
该合作研究计划的最终目标是确定抗疟临床候选药物
异氰萜烯醇家族的类似物,是一类正在研究中的天然产物,具有有效的功效
对恶性疟原虫具有活性,恶性疟原虫是人类最致命的疟疾的病原体。药物
耐药性仍然是阻碍全球控制疟疾感染努力的主要因素,降低了疟疾感染率
死亡率并降低治疗费用。对抗疟疾耐药性需要开发
以前未用于疟疾治疗的新型化学物质,以及新治疗方法的实施
最佳使用这些化学物质以防止耐药性的策略。我们生成的初步数据
实验室支持这项研究的前提,即 kalihinols 可以开发为新型抗疟药
代理。我们的数据表明 (i) kalihinol 天然产物对血液阶段具有有效的活性
IC50 值在低纳摩尔范围内的药物敏感型和耐药型恶性疟原虫菌株,(ii)
这些化合物适合快速和简化的合成路线,产生保留有效活性的类似物
抗疟活性,(iii) 它们是安全的,具有高治疗指数,(iv) 它们的异腈官能团是
代谢相对稳定,并且(v)它们可以通过一种新的作用模式发挥其抗疟活性。
基于这些数据,我们建议深入研究这些数据的结构-活动关系
化合物,表征其体外和体内功效和安全性,并揭示其作用模式。瞄准
1、我们将进一步表征铅kalihinol类似物的生物活性和药理特性
已经掌握的技术,包括抑制药物敏感和耐药疟原虫生长的能力
在人类红细胞内,阻止性别分化和传播给蚊子,并消除
小鼠致命的疟疾感染。在目标 2 中,我们将采用通用化学合成设计,允许
获得许多不同的 kalihinol 型化合物,目的是优化效力和药理学
属性。具有优异效力、选择性和安全性的化合物将在体内进一步评估
功效和安全性。在目标 3 中,药物的作用方式和寄生虫的可能机制
将使用最先进的细胞、代谢、化学生物学进一步阐明对它们的抵抗力
和基因组学方法。这个协作和多学科项目与人类健康相关
因为它有可能基于一类新型化学物质产生新的临床前抗疟药物
以前从未用于疟疾治疗。
英文摘要
Project Summary
Hit-to-Lead Development of the Kalihinol Scaffold for Malaria Treatment
The ultimate goal of this collaborative research program is to identify antimalarial clinical candidates among
analogues of the kalihinol family of isocyanoterpenes, an understudied class of natural products with potent
activity against Plasmodium falciparum, the causative agent of the deadliest form of human malaria. Drug
resistance remains the leading factor hampering global efforts aimed at controlling malaria infection, lowering
mortality rates and reducing the cost of treatment. Countering malaria drug resistance requires development of
novel classes of chemicals not previously used in malaria therapy, and implementation of novel therapeutic
strategies for optimal use of these chemicals to prevent drug resistance. Preliminary data generated in our
laboratories support the premise of this research that the kalihinols could be developed as novel antimalarial
agents. Our data demonstrate that (i) kalihinol natural products have potent activity against blood stages of
both drug-sensitive and drug-resistant P. falciparum strains with IC50 values in the low nanomolar range, (ii)
these compounds are amenable to rapid and simplified synthesis routes producing analogues that retain potent
antimalarial activity, (iii) they are safe, with high therapeutic indices, (iv) their isonitrile functional groups are
relatively stable to metabolism, and (v) they may exert their antimalarial activity through a novel mode of action.
Building upon this body of data, we propose to delve deeply into the structure-activity relationship of these
compounds, characterize their in vitro and in vivo efficacy and safety, and unravel their mode of action. In Aim
1, we will further characterize the biological activity and pharmacological properties of lead kalihinol analogues
already in hand, including their ability to inhibit growth of drug-sensitive and drug-resistant malaria parasites
within human red blood cells, to block sexual differentiation and transmission to mosquitoes, and to eliminate
lethal malaria infection in mice. In Aim 2, we will embrace a general chemical synthesis design that permits
access to many diverse kalihinol-type compounds, with the goal of optimizing potency and pharmacological
properties. Compounds with excellent potency, selectivity and safety profiles will be further evaluated in vivo for
efficacy and safety. In Aim 3. both the mode of action of the drugs and the parasite's possible mechanisms of
resistance against them will be further elucidated using state-of-the-art cellular, metabolic, chemical biology
and genomics approaches. This collaborative and multidisciplinary project is of relevance to human health
because of its potential to produce new preclinical antimalarial leads based on a novel class of chemicals
never before used in malaria therapy.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Fosinopril analogs for the treatment of human babesiosis
-
批准号:10396069
-
项目类别:
-
资助金额:$72.59万
-
财政年份:2021
-
负责人:CHOUKRI BEN MAMOUN
-
依托单位:
Fosinopril analogs for the treatment of human babesiosis
-
批准号:10211812
-
项目类别:
-
资助金额:$74.28万
-
财政年份:2021
-
负责人:CHOUKRI BEN MAMOUN
-
依托单位:
Fosinopril analogs for the treatment of human babesiosis
-
批准号:10594970
-
项目类别:
-
资助金额:$72.59万
-
财政年份:2021
-
负责人:CHOUKRI BEN MAMOUN
-
依托单位:
Antigen Discovery and Vaccine Development for Human Babesia Parasites
-
批准号:10386919
-
项目类别:
-
资助金额:$41.88万
-
财政年份:2020
-
负责人:CHOUKRI BEN MAMOUN
-
依托单位:
Antigen Discovery and Vaccine Development for Human Babesia Parasites
-
批准号:10163799
-
项目类别:
-
资助金额:$41.88万
-
财政年份:2020
-
负责人:CHOUKRI BEN MAMOUN
-
依托单位:
Antigen Discovery and Vaccine Development for Human Babesia Parasites
-
批准号:10609400
-
项目类别:
-
资助金额:$41.88万
-
财政年份:2020
-
负责人:CHOUKRI BEN MAMOUN
-
依托单位:
Hit-to-Lead Development of the Kalihinol Scaffold for Malaria Treatment
-
批准号:10228612
-
项目类别:
-
资助金额:$70.65万
-
财政年份:2018
-
负责人:CHOUKRI BEN MAMOUN
-
依托单位:
Development of endochin-like quinolones for babesiosis therapy
-
批准号:9392521
-
项目类别:
-
资助金额:$66.94万
-
财政年份:2016
-
负责人:CHOUKRI BEN MAMOUN
-
依托单位:
Probing the natural genomic diversity of Babesia microti
-
批准号:9064063
-
项目类别:
-
资助金额:$24.98万
-
财政年份:2015
-
负责人:CHOUKRI BEN MAMOUN
-
依托单位:
Development of novel therapeutics for Babesia microti infection
-
批准号:8865547
-
项目类别:
-
资助金额:$24.98万
-
财政年份:2014
-
负责人:CHOUKRI BEN MAMOUN
-
依托单位:
Development of novel therapeutics for Babesia microti infection
-
批准号:8773222
-
项目类别:
-
资助金额:$20.81万
-
财政年份:2014
-
负责人:CHOUKRI BEN MAMOUN
-
依托单位:
Function and Inhibition of Plasmodium Lipid Decarboxylases
-
批准号:8373669
-
项目类别:
-
资助金额:$42.58万
-
财政年份:2012
-
负责人:CHOUKRI BEN MAMOUN
-
依托单位:
Function and Inhibition of Plasmodium Lipid Decarboxylases
-
批准号:8686736
-
项目类别:
-
资助金额:$40.98万
-
财政年份:2012
-
负责人:CHOUKRI BEN MAMOUN
-
依托单位:
Function and Inhibition of Plasmodium Lipid Decarboxylases
-
批准号:9088297
-
项目类别:
-
资助金额:$40.95万
-
财政年份:2012
-
负责人:CHOUKRI BEN MAMOUN
-
依托单位:
Function and Inhibition of Plasmodium Lipid Decarboxylases
-
批准号:8879955
-
项目类别:
-
资助金额:$40.97万
-
财政年份:2012
-
负责人:CHOUKRI BEN MAMOUN
-
依托单位:
Function and Inhibition of Plasmodium Lipid Decarboxylases
-
批准号:8488406
-
项目类别:
-
资助金额:$38.54万
-
财政年份:2012
-
负责人:CHOUKRI BEN MAMOUN
-
依托单位:
Transcriptional Regulators of the Malarial var Multigene Family
-
批准号:7791180
-
项目类别:
-
资助金额:$25.9万
-
财政年份:2010
-
负责人:CHOUKRI BEN MAMOUN
-
依托单位:
Transcriptional Regulators of the Malarial var Multigene Family
-
批准号:8088124
-
项目类别:
-
资助金额:$20.7万
-
财政年份:2010
-
负责人:CHOUKRI BEN MAMOUN
-
依托单位:
NUCLEOSIDE TRANSPORTERS
-
批准号:7719126
-
项目类别:
-
资助金额:$0.29万
-
财政年份:2008
-
负责人:CHOUKRI BEN MAMOUN
-
依托单位:
MALARIA
-
批准号:7719093
-
项目类别:
-
资助金额:$0.25万
-
财政年份:2008
-
负责人:CHOUKRI BEN MAMOUN
-
依托单位:
海外基金