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

• 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
• 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

 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。常用的抗疟药都不能有效对抗疟原虫配子细胞（负责传播的寄生虫阶段），因此患者在症状消失后仍可保持传染性数周。我们最近筛选了超过 6000 种生物活性分子，包括 400 种疟疾盒化合物，鉴定出 7 种对 III-V 期配子体的 IC50 < 50nM。其中之一，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 倍以上。 Torin 2 对另外 2 种恶性疟原虫菌株 HB3 和 Dd2 也同样有效，它们具有不同的地理起源和耐药性。重要的是，使用小鼠伯氏疟原虫模型测试体内传播阻断活性，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 Torin 2 相互作用蛋白。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 Torin 2 抑制从红细胞内发育到子孢子形成的阶段特异性和时间，为药物输送策略和机制研究提供信息。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。此外，为了推进我们目前对配子体活力所需的细胞途径的有限了解，这些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。