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，每年在全球范围内感染200-3亿人。它是由质子属的四个单细胞寄生虫中的任何一个中的任何一个感染红细胞引起的。当由恶性疟原虫引起时，疟疾正在威胁生命，导致1-200万人死亡，主要是幼儿。当前的寄生虫耐药性增加，开发疫苗的努力受到疟原虫生命周期的严重限制。因此，需要新的治疗方法。最近测序的最致命性疟疾寄生虫疟原虫恶性疟原虫的基因组揭示了与哺乳动物和氰基杆菌中与碳酸氢盐反应性可溶性腺苷环酶（SAC）相关的两个腺苷环酶基因（PFAC）。他们的序列预测PFAC是碳酸氢盐反应性的，我们假设至少有一个是疟原虫对高水平二氧化碳/碳酸氢盐的绝对依赖性，以实现生存能力。因此，PFAC可以代表抗疟药的新靶标。我们用小分子（KH7）处理了恶性疟原虫，我们开发了迄今为止抑制了所有已测试的类似SAC样的循环酶，包括在哺乳动物，单细胞真核生物和细菌中发现的类似囊样的循环酶。在单个细胞周期内，在红细胞中培养的寄生虫以剂量依赖性杀死。对囊样循环酶惰性的结构相关化合物（KH7.15）对寄生虫生长没有影响。在此赠款应用中，我们建议克隆并表征两个PFAC循环酶，并确认它们是否是KH7致死性的靶标。如果将PFAC验证为新抗疟药的靶标，我们建议使用纯化的质质环酶筛选化学文库，以鉴定相对于人类囊的质质循环酶选择性的化合物。