New target for malaria drug development

疟疾药物开发的新目标

• 批准号: 6911385
• 负责人: LONNY R LEVIN
• 金额: $ 33.6万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6911385
• 关键词: Plasmodium falciparum; adenylate cyclase; antimalarial agents; bicarbonates; carbon dioxide; combinatorial chemistry; drug design /synthesis /production; drug discovery /isolation; enzyme inhibitors; gene expression; malaria; microorganism culture; microorganism metabolism; molecular cloning; protozoal genetics; small molecule

DESCRIPTION (provided by applicant): Malaria is vector-borne disease infecting 200-300 million people per year worldwide. It is caused by infection of red blood cells by any one of four unicellular parasites from the genus Plasmodium. When caused by Plasmodium falciparum, malaria is life threatening, resulting in 1-2 million deaths, primarily in young children. Current treatments suffer from increasing resistance among parasites and efforts to develop a vaccine are severely limited by the Plasmodium life cycle; therefore, new treatments are needed. The recently sequenced genome of the most lethal malarial parasite, Plasmodium falciparum, revealed two adenylyl cyclase genes (PfACs) related to the bicarbonate responsive soluble adenylyl cyclases (sAC) in mammals and cyanobacteria. Their sequences predict the PfACs to be bicarbonate responsive, and we hypothesized that at least one is responsible for Plasmodium's absolute dependence on high levels of carbon dioxide/bicarbonate for viability. Therefore, the PfACs may represent new targets for an antimalarial drug. We treated P. falciparum with a small molecule (KH7) we developed which inhibits all sAC-like cyclases tested thus far, including sAC-like cyclases found in mammals, unicellular eukaryotes and bacteria. Parasites cultured in red blood cells were killed by KH7 in a dose dependent manner within a single cell cycle. A structurally related compound (KH7.15) which is inert towards sAC-like cyclases had no effect on parasite growth. In this grant application, we propose to clone and characterized the two PfAC cyclases and confirm whether they are the target of KH7 lethality. If the PfACs are validated as targets for new antimalarial drugs, we propose to use purified Plasmodium cyclases to screen a chemical library to identify compounds selective for Plasmodium cyclases relative to human sAC.

描述（由申请人提供）：疟疾是媒介传播的疾病，每年感染全世界 200-3 亿人。它是由疟原虫属四种单细胞寄生虫中的任何一种感染红细胞引起的。当疟疾由恶性疟原虫引起时，会危及生命，导致 1-200 万人死亡，其中主要是幼儿。目前的治疗方法面临着寄生虫耐药性不断增加的问题，而开发疫苗的努力也受到疟原虫生命周期的严重限制；因此，需要新的治疗方法。最近对最致命的疟疾寄生虫恶性疟原虫的基因组进行了测序，揭示了两个与哺乳动物和蓝细菌中碳酸氢盐反应性可溶性腺苷酸环化酶（sAC）相关的腺苷酸环化酶基因（PfAC）。它们的序列预测 PfAC 对碳酸氢盐有反应，我们假设至少有一种 PfAC 导致疟原虫的生存能力绝对依赖于高水平的二氧化碳/碳酸氢盐。因此，PfACs可能代表抗疟药物的新靶点。我们用我们开发的小分子 (KH7) 治疗恶性疟原虫，该小分子抑制迄今为止测试的所有 sAC 样环化酶，包括在哺乳动物、单细胞真核生物和细菌中发现的 sAC 样环化酶。在红细胞中培养的寄生虫在单个细胞周期内被 KH7 以剂量依赖性方式杀死。结构相关的化合物 (KH7.15) 对 sAC 样环化酶呈惰性，对寄生虫的生长没有影响。在本次资助申请中，我们建议克隆和表征两种 PfAC 环化酶，并确认它们是否是 KH7 致死的目标。如果 PfAC 被验证为新型抗疟药物的靶点，我们建议使用纯化的疟原虫环化酶来筛选化学库，以鉴定相对于人类 sAC 对疟原虫环化酶具有选择性的化合物。