Development of Malaria Transmission-Blocking Drugs

疟疾传播阻断药物的开发

• 批准号: 10685880
• 负责人: Philip Sanderson
• 金额: $ 189.73万
• 依托单位: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10685880
• 关键词: Affect; Africa South of the Sahara; Antimalarials; Biological Assay; Bite; Chills; Culicidae; Data; Development; Diarrhea; Disease; Dose; Drug Kinetics; Evaluation; FRAP1 gene; Fever; Goals; Headache; Infection prevention; Lead; Malaria; Modeling; Myalgia; National Center for Advancing Translational Sciences; Organ; Parasite Control; Parasites; Parasitic Diseases; Patients; Persons; Pharmaceutical Preparations; Pilot Projects; Plasmodium falciparum; Recovery; Research Personnel; Rodent; Scientist; Series; Sweating; Symptoms; Testing; Time; Vomiting; Work; analog; design; in vivo; lead optimization; malaria transmission; mosquito-borne; novel drug class; reduce symptoms; transmission process

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.

即使在当前的疗法上，疟疾患者在一段时间内仍然具有感染性，从而可以进一步向他人传播。控制寄生虫的传播对于消除和消除疟疾至关重要。但是，大多数抗疟药并不活跃于称为配子细胞的恶性疟原虫寄生虫，这是导致疟疾通过蚊子传播到一个人到一个人的传播。 为了开始填补这一空隙，研究人员筛选了5,215种已知的生物活性化合物和批准的摄入量化药物。一种具有良好药代动力学（TORIN2）的化合物被选为进一步评估的第一个候选者，包括在体内啮齿动物疟疾传播模型中进行测试。两种4 mg/kg剂量完全阻断了寄生虫感染蚊子的能力，2 mg/kg剂量会局部阻断，从而证实了Torin2的传输阻滞活性。 初步数据表明，恶性疟原虫中的Torin2靶标与哺乳动物靶标不同，从而设计了疟疾特异性衍生物。主要合作者和NCATS科学家之间的试点研究使用了配子细胞生存力测定，细胞MTOR分析和体内啮齿动物疟疾传播模型来鉴定新的疟疾特异性多素类似物。 这项工作导致鉴定一系列适合铅优化的化合物。该项目目前处于晚期铅优化的状态，目的是识别具有单剂量活性的化合物针对疾病的所有阶段。