A new target for malaria drug development

疟疾药物开发的新目标

• 批准号: 7327787
• 负责人: LONNY R LEVIN
• 金额: $ 31.25万
• 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/7327787
• 关键词: Adenylate Cyclase; Antigens; Antimalarials; Applications Grants; Bacteria; Bicarbonates; Biochemical; Biological; Biology; Buffers; Candida albicans; Carbon Dioxide; Cell Cycle; Cells; Cessation of life; Chemicals; Child; Chloroflexi; Collaborations; Condition; Cyanobacterium; Dependence; Developed Countries; Developing Countries; Dose; Effectiveness; Emerging Communicable Diseases; Enzymes; Equilibrium; Erythrocytes; Eukaryota; Eukaryotic Cell; Falciparum Malaria; GTP-Binding Proteins; Genes; Genus Mycobacterium; Growth; Healthcare; Human; Immunology; Infection; Laboratories; Lead; Libraries; Life; Life Cycle Stages; Malaria; Mammals; Medical; Microbiology; Organism; Pan Genus; Parasites; Personal Communication; Pharmaceutical Preparations; Physiological; Plasmodium; Plasmodium falciparum; Regulation; Relative (related person); Research Personnel; Resistance; Resistance development; Resources; Sea Urchins; Signal Pathway; Small Molecule Chemical Library; Surface; System; Testing; Therapeutic; Vaccines; Vector-transmitted infectious disease; adenylyl cyclase 6; college; combinatorial; cost effective; drug development; gene cloning; genome sequencing; inhibitor/antagonist; killings; small molecule; small molecule libraries

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(申请人提供)：疟疾是一种媒介传播的疾病，每年感染全球2-3亿人。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。由恶性疟原虫引起的疟疾危及生命，导致100-200万人死亡，主要是幼儿。目前的治疗方法受到寄生虫耐药性增加的困扰，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。最近对恶性疟原虫的基因组测序发现，哺乳动物和蓝藻中有两个与重碳酸盐反应的可溶腺苷酸环化酶(SAC)相关的腺酰环化酶基因(PfACs)。它们的序列预测PfAC对碳酸氢盐有反应，我们假设至少有一个是疟原虫绝对依赖高水平的二氧化碳/碳酸氢盐生存的原因。因此，Pfacs可能是抗疟疾药物的新靶点。我们用我们开发的小分子(Kh7)治疗恶性疟原虫，这种小分子可以抑制到目前为止测试的所有SAC样环酶，包括在哺乳动物、单细胞真核生物和细菌中发现的SAC样环酶。在单个细胞周期内，Kh7以剂量依赖的方式杀死红血球中培养的寄生虫。一种结构相关的化合物(KH7.15)对SAC样环酶不起作用，对寄生虫的生长没有影响。在这项拨款申请中，我们建议克隆和鉴定两个Pfac环化酶，并确认它们是否是Kh7致死的靶标。如果PfAC被确认为新的抗疟疾药物的靶标，我们建议使用纯化的疟原虫环化酶来筛选一个化学库，以确定相对于人SAC对疟原虫环化酶具有选择性的化合物。

项目成果

Crystal structure and regulation mechanisms of the CyaB adenylyl cyclase from the human pathogen Pseudomonas aeruginosa.

人类病原体铜绿假单胞菌 CyaB 腺苷酸环化酶的晶体结构和调节机制。

• DOI: 10.1016/j.jmb.2011.12.045
• 发表时间: 2012
• 期刊: Journal of molecular biology
• 影响因子: 5.6
• 作者: Topal,Hüsnü;Fulcher,NanetteB;Bitterman,Jacob;Salazar,Eric;Buck,Jochen;Levin,LonnyR;Cann,MartinJ;Wolfgang,MatthewC;Steegborn,Clemens
• 通讯作者: Steegborn,Clemens