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
项目摘要
治疗疟疾的卡利辛诺支架的发展
这一合作研究计划的最终目标是确定以下抗疟疾临床候选对象
异氰基萜烯的Kalihinol家族的类似物,这是一类未被研究的天然产物,具有
对恶性疟原虫的活性,恶性疟原虫是人类最致命的疟疾的病原体。药效
耐药性仍然是阻碍旨在控制疟疾感染的全球努力的主要因素,
降低死亡率和降低治疗成本。对抗疟疾抗药性需要发展
以前未用于疟疾治疗的新型化学物质,以及新型治疗方法的实施
最佳使用这些化学品以防止抗药性的战略。生成的初步数据在我们的
实验室支持这项研究的前提,即卡利欣酚可以被开发为新的抗疟疾药物
探员们。我们的数据表明:(I)卡利胡酚天然产物对血液病具有很强的抑制作用。
对药物敏感和耐药的恶性疟原虫,其IC50值均在低纳摩尔范围内,(Ii)
这些化合物易于快速和简化的合成路线,产生保持效力的类似物
抗疟疾活性,(3)它们是安全的,具有高治疗指数,(4)它们的异腈官能团是
它们对新陈代谢相对稳定;(V)它们可能通过新的作用模式发挥抗疟疾活性。
在这些数据的基础上,我们建议深入研究这些化合物的结构-活性关系
化合物,表征它们在体外和体内的有效性和安全性,并揭示它们的作用模式。在AIM
1,我们将进一步表征铅Kalihinol类似物的生物活性和药理性质。
已经掌握,包括它们抑制药物敏感和抗药性疟疾寄生虫生长的能力
在人类红细胞内,阻断性分化和传播给蚊子,并消除
致命的小鼠疟疾感染。在目标2中,我们将采用通用的化学合成设计,允许
获得多种不同的卡利辛酚类化合物,目的是优化效力和药理作用
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
有效性和安全性。目的3.药物的作用方式和寄生虫可能的作用机制。
对它们的耐药性将使用最先进的细胞、代谢、化学生物学来进一步阐明
以及基因组学方法。这一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的化学物质产生新的临床前抗疟疾先导化合物
从未在疟疾治疗中使用过。
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.
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