Advancing gametocytocidal agents as drugs against P. falciparum

推进杀配子细胞药物作为对抗恶性疟原虫的药物

基本信息

批准号：
8963206
负责人：
Kim C Williamson
金额：
$ 5.67万
依托单位：
LOYOLA UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2015-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8963206
关键词：
Affect Antimalarials Binding Biological Assay Boxing Candidate Disease Gene Cells Clinical Collaborations Complement Coupled Culicidae Data Defect Development Disease Dose Drug Delivery Systems Drug Design Drug Exposure Drug resistance Enzymes Exposure to Expression Library Family Funding Genes Germ Cells Goals HepG2 Homologous Gene Hour Human In Vitro Infection Inhibitory Concentration 50 Lead Liver Longevity Malaria Metabolic Pathway Modeling Monitor Mus Mutation Oocysts Parasite resistance Parasites Pathway interactions Patients Pattern Peptide Hydrolases Persons Pharmaceutical Preparations Phosphotransferases Plant Resins Plasmodium Plasmodium falciparum Population Production Proteasome Inhibitor Protein-Serine-Threonine Kinases Proteins Recombinant Proteins Reporting Research Personnel Resistance Resistance profile Ribose-Phosphate Pyrophosphokinase Rodent Role Saccharomyces cerevisiae Specificity Sporozoites Staging Structure-Activity Relationship Symptoms Testing Therapeutics for Rare and Neglected Diseases Time Translational Research Transport Process Vesicle Work analog asexual base cytotoxicity test epoxomicin feeding human FRAP1 protein in vitro testing in vivo inorganic phosphate interest killings malaria transmission member miniaturize mouse model novel nucleotide metabolism overexpression protein expression public health relevance research study trafficking transmission process

项目摘要

DESCRIPTION (provided by applicant): New strategies are needed to block malaria transmission and eradicate the spread of the disease. None of the commonly used antimalarials are effective against Plasmodium gametocytes, the parasite stage responsible for transmission, and consequently patients can remain infectious for weeks after symptoms have resolved. Our recent screen of > 6000 bioactive molecules, including 400 malaria box compounds identified 7 with < 50nM IC50 against stage III-V gametocytes. One of these, Torin 2 had an IC50 of 8 nM against P. falciparum strain 3D7, which is >1000 times lower than its activity against the mammalian HepG2 cell line. Torin 2 was also equally effective against 2 additional P. falciparum strains, HB3 and Dd2, with distinct geographic origins and drug resistance profiles. Importantly, two 4mg/kg doses completely blocked oocyst formation using the mouse P. berghei model to test in vivo transmission blocking activity. Early structure activity relationship (SAR) analysis done in collaboration with investigators at the National Center for Advancing Translational Research (NCATS) allowed the production of a Torin 2 resin that lead to the identification of Torin 2 interacting proteins. The goals of this proposal are to extend our analysis of Torin 2 by: Aim 1: Define the stage specificity and timing of Torin 2 inhibition from intraerythrocytic development to sporozoite formation to inform both drug delivery strategies and mechanistic studies. Aim 2: Evaluate the in vivo activity of novel Torin 2 analogs using the rodent malaria model: Aim 3: Evaluate the Plasmodium target and mechanism of Torin 2 gametocytocidal activity using both directed and discovery approaches. In addition, to advancing our currently limited understanding of the cellular pathways required for gametocyte viability, the results will provide important new leads for the development of a potent malaria transmission-blocking drug.

描述（由申请人提供）：需要新的策略来阻止疟疾传播并根除该疾病的传播。常用的抗疟药均不能有效对抗疟原虫配子体（负责传播的寄生虫阶段），因此患者可能会在数周内保持传染性。我们最近对超过 6000 种生物活性分子（包括 400 种疟疾盒化合物）进行了筛选，鉴定出其中 7 种对 III-V 期配子细胞的 IC50 值 < 50nM。 Torin 2 对恶性疟原虫菌株 3D7 的 IC50 为 8 nM，比其对哺乳动物 HepG2 细胞系的活性低 >1000 倍，Torin 2 对另外 2 种恶性疟原虫菌株 HB3 和 Dd2 也同样有效。，具有不同的地理起源和耐药性特征，重要的是，使用小鼠伯氏疟原虫模型，两次 4mg/kg 剂量完全阻断了卵囊形成。与国家推进转化研究中心 (NCATS) 的研究人员合作进行的早期结构活性关系 (SAR) 分析允许生产 Torin 2 树脂，从而鉴定出相互作用的 Torin 2 蛋白。该提案的目标是通过以下方式扩展我们对 Torin 2 的分析：目标 1：定义从红细胞内发育到子孢子形成的 Torin 2 抑制的阶段特异性和时间安排，为两种药物递送策略提供信息目标 2：使用啮齿动物疟疾模型评估新型 Torin 2 类似物的体内活性：目标 3：使用定向和发现方法评估疟原虫靶标和 Torin 2 杀配子细胞活性的机制。目前对配子体活力所需的细胞途径的了解有限，该结果将为开发有效的疟疾传播阻断药物提供重要的新线索。