Targeting P. falciparum gametocytes for drug development

针对恶性疟原虫配子细胞进行药物开发

• 批准号: 8355671
• 负责人: Kim C Williamson
• 金额: $ 20.81万
• 依托单位: LOYOLA UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8355671
• 关键词: Address; Affect; AlamarBlue; Anabolism; Anions; Antimalarials; Apoptosis Regulation Gene; Area; Biochemistry; Biological Assay; Biological Process; Biology; Cell Line; Cessation of life; Chloroquine; Critical Pathways; Culicidae; DNA biosynthesis; Development; Digestion; Disease; Drug resistance; Fansidar; Future; Gametogenesis; Goals; Hemoglobin; Incidence; Inhibitory Concentration 50; Ion Channel; Lead; Libraries; Malaria; Mammalian Cell; Metabolic Pathway; Metabolism; Monitor; Morbidity - disease rate; Morphology; Mus; Parasites; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Phosphotransferases; Physiology; Plasmodium berghei; Plasmodium falciparum; Population; Preclinical Drug Evaluation; Process; Pyrimethamine-Sulfadoxine; Pyrimidine; Regimen; Reporting; Research; Resistance; Rodent; Screening procedure; Signal Transduction; Staging; Surface; Testing; Therapeutic Index; Time; analog; asexual; base; chemotherapy; cytotoxicity; design; disease transmission; drug development; drug discovery; drug use screening; epoxomicin; global health; hemozoin; high throughput screening; indexing; inhibitor/antagonist; insight; killings; lipid metabolism; mortality; novel; resistance mechanism; response; safety testing; transmission process; treatment program

DESCRIPTION (provided by applicant): Malaria is a tropical parasitological disease that remains a global health problem, causing ~.8 million deaths and 250 million cases annually. Expanded control and treatment programs in the past decade have reduced the incidence of the disease and lead to the call for efforts to eliminate, possibly even eradicate, malaria. To do this new strategies are needed that target the sexual stages of the parasites, which are responsible for disease transmission. The current recommended chemotherapy for malaria does not effectively kill mature gametocytes, allowing malaria to be transmitted for more than a week after the clearance of asexual parasites. Previous drug screens used assays that only detected asexual replication and therefore did not monitor activity against gametocytes. We have recently developed a gametocytocidal assay that can be used to screen against both early and late stage gametocytes. The goal of this exploratory R21 proposal is twofold 1) to analyze to the gametocytocidal activity of novel compounds recently found to kill asexual parasites in a high throughput screen and 2) to identify metabolic pathways that are essential for the propagation and spread of gametocytes by screening a library of pharmacologically active inhibitors with known targets. Together these approaches should identify classes of compounds that can be targeted for further drug development, as well as advance our understanding of gametocyte metabolism and facilitate the design of effective control strategies. PUBLIC HEALTH RELEVANCE: The long term goal of this research is to develop drugs that can block malaria transmission from one person to another. Forty percent of the world's population lives in malaria endemic areas and the commonly used antimalarials are not effective against the stages of the parasite that are responsible for the spread of the disease. Drugs that effectively reduce the transmission of malaria will decrease morbidity and mortality, as well as contribute to malaria elimination and eradication efforts.

描述（由申请人提供）：疟疾是一种热带寄生虫病，仍然是一个全球性健康问题，每年造成约 800 万人死亡和 2.5 亿病例。过去十年扩大的控制和治疗计划减少了该疾病的发病率，并导致人们呼吁努力消除甚至可能根除疟疾。要做到这一点 需要针对导致疾病传播的寄生虫的性阶段的新策略。目前推荐的疟疾化疗并不能有效杀死成熟的配子体，导致疟疾在无性寄生虫清除后仍可传播一周以上。以前的药物筛选使用的测定法仅检测无性复制，因此不监测针对配子体的活性。我们最近开发了一种杀配子细胞测定法，可用于筛选早期和晚期配子细胞。这一探索性 R21 提案的目标有两个：1）分析最近发现的高通量筛选中杀死无性寄生虫的新型化合物的杀配子细胞活性；2）通过筛选具有已知靶点的药理学活性抑制剂库，确定对配子体繁殖和传播至关重要的代谢途径。这些方法共同应确定可用于进一步药物开发的化合物类别，并增进我们对配子体代谢的理解并促进有效控制策略的设计。 公共卫生相关性：这项研究的长期目标是开发能够阻止疟疾从一个人传播到另一个人的药物。世界上百分之四十的人口生活在疟疾流行地区，常用的抗疟药对导致疾病传播的寄生虫阶段无效。有效减少疟疾传播的药物将降低发病率和死亡率，并有助于消除和根除疟疾的努力。