Advancing gametocytocidal agents as drugs against P. falciparum

 描述（由申请人提供）：需要新的策略来阻断疟疾传播并根除疾病的传播。没有一种常用的抗疟药对疟原虫配子体有效，疟原虫配子体是负责传播的寄生虫阶段，因此患者在症状消退后仍能保持感染性数周。我们最近筛选了> 6000种生物活性分子，包括400种疟疾盒化合物，其中7种对III-V期配子母细胞的IC 50 <50 nM。其中之一，Torin 2对恶性疟原虫菌株3D 7的IC 50为8 nM，这比其对哺乳动物HepG 2细胞系的活性低>1000倍。Torin 2对另外2种恶性疟原虫菌株HB 3和Dd 2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，使用小鼠伯氏疟原虫模型测试体内传播阻断活性，两个4 mg/kg剂量完全阻断卵囊形成。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：目的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，以告知药物递送策略和机制研究。目标二：使用啮齿动物疟疾模型评价新型Torin 2类似物的体内活性：目的3：使用定向和发现方法评价Torin 2杀配子细胞活性的疟原虫靶标和机制。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理解，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。

 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.