Advancing gametocytocidal agents as drugs against P. falciparum

 描述(由申请人提供)：需要新的战略来阻止疟疾传播和根除疾病的传播。常用的抗疟药都不能有效地对抗疟原虫配子体，配子体是负责传播的寄生虫阶段，因此，患者在症状缓解后仍可感染数周。我们最近对&gt；6000生物活性分子进行了筛选，其中包括400种疟疾盒化合物，其中7种化合物对III-V期配子细胞具有50 nm的IC50。其中，Torin 2对恶性疟原虫3D7株的IC50为8 NM，比其对哺乳动物细胞株HepG2的IC50低1000倍。Torin 2对另外两个恶性疟原虫菌株HB3和DD2也同样有效，它们具有不同的地理来源和耐药性特征。重要的是，两个4 mg/kg的剂量完全阻止了卵囊的形成，使用小鼠伯氏疟原虫模型来测试体内传播阻断活性。与国家高级翻译研究中心(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。这项建议的目的是通过以下方式扩展我们对Torin 2的分析：目的1：确定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机，为药物传递策略和机制研究提供信息。目的2：用鼠疟疾模型评价新型Torin-2类似物的体内活性：目的3：用直接法和发现法评价Torin-2配子体杀灭活性的作用靶点和机制。此外，为了促进我们目前对配子体存活所需的细胞途径的有限理解，该结果将为开发一种有效的疟疾传播阻断药物提供重要的新线索。

 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.