Development of Malaria Transmission-Blocking Drugs

即使在目前的治疗方法下，疟疾患者在一段时间内仍具有传染性，从而允许进一步通过蚊子传播给其他人。控制寄生虫传播对于消灭和根除疟疾至关重要。然而，大多数抗疟疾药物对称为配子体的有性期恶性疟原虫不起作用，配子体是疟疾通过蚊子在人与人之间传播的罪魁祸首。 为了开始填补这一空白，研究人员筛选了5215种已知的生物活性化合物，并批准了具有配子细胞杀灭活性的药物。一种具有良好药代动力学的化合物(Torin2)被选为进一步评估的第一候选药物，包括在活体啮齿动物疟疾传播模型中进行测试。两个4 mg/kg剂量完全阻断了寄生虫感染蚊子的能力，2 mg/kg剂量部分阻断，证实了Torin2的传播阻断活性。 初步数据表明，恶性疟原虫中的Torin2靶标与哺乳动物的靶标不同，这使得可以设计疟疾特异的衍生品。主要合作者和NCATS科学家之间的初步研究使用配子体活性分析、细胞mTOR分析和啮齿动物疟疾体内传播模型来确定新的疟疾特异性Torin2类似物。这项工作导致了一系列适合于铅优化的化合物的鉴定。该项目目前处于后期主导优化阶段，目标是确定一种具有单剂量活性的化合物，用于治疗疾病的所有阶段。

Even while on current therapies, malaria patients remain infectious for a period of time, allowing further mosquito-borne transmission to others. Control of parasite transmission is critical for elimination and eradication of malaria. However, most antimalarial drugs are not active against sexual stage P. falciparum parasites called gametocytes which are responsible for the spread of malaria from person to person via mosquitoes. To begin to fill this void, investigators screened 5,215 known bioactive compounds and approved drugs for gametocytocidal activity. One compound with favorable pharmacokinetics (Torin2) was selected as the first candidate for further evaluation, including testing in an in vivo rodent malaria transmission model. Two 4 mg/kg doses completely blocked parasites ability to infect mosquitoes, and a 2 mg/kg dose gave a partial blockade, confirming the transmission-blocking activity of Torin2. Preliminary data indicate that the Torin2 target in P. falciparum is distinct from the mammalian target, allowing the design of malaria-specific derivatives. Pilot studies between the lead collaborator and NCATS scientists used a gametocyte viability assay, a cellular mTOR assay and an in vivo rodent malaria transmission model to identify new malaria-specific Torin2 analogues. This work resulted in identification of a series of compounds suitable for lead optimization. The project currently is in late-stage lead optimization, with the goal of identifying a compound with single-dose activity against all stages of the disease.