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: 8496707
• 负责人: Kim C Williamson
• 金额: $ 16.63万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8496707
• 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; 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; screening; 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.

描述（由申请人提供）：疟疾是一种热带寄生虫疾病，仍然是一个全球健康问题，每年造成约80万人死亡和2.5亿例病例。在过去的十年中，扩大的控制和治疗计划降低了疾病的发病率，并呼吁努力消除，甚至可能消除疟疾。为此 需要采取新的策略来针对寄生虫的性阶段，这是造成疾病传播的原因。当前的疟疾推荐化学疗法不会有效地杀死成熟的配子细胞，从而使疟疾在清除无性寄生虫后的一周以上传播。先前的药物筛查使用的测定法仅检测到无性复制，因此未监测针对配子细胞的活动。我们最近开发了一种配子型测定法，可用于与早期和晚期配子细胞进行筛查。该探索性R21提案的目的是两倍1）分析最近发现在高吞吐量屏幕中杀死无性寄生虫的新型化合物的摄影性活性和2）2）2），以通过筛选具有与已知的药理学抑制器的库库的传播和传播相关的代谢途径，这对于繁殖和传播，这对于具有众所周知的药理学抑制者的库来繁殖和传播。这些方法共同确定可以针对进一步药物开发的化合物类别，并促进我们对配子体代谢的理解，并促进有效控制策略的设计。

项目成果

Potent Plasmodium falciparum gametocytocidal activity of diaminonaphthoquinones, lead antimalarial chemotypes identified in an antimalarial compound screen.

二氨基萘醌具有有效的恶性疟原虫配子细胞杀灭活性，二氨基萘醌是抗疟化合物筛选中鉴定出的主要抗疟化学型。

• DOI: 10.1128/aac.01930-13
• 发表时间: 2015
• 期刊: Antimicrobial agents and chemotherapy
• 影响因子: 4.9
• 作者: Tanaka,TakeshiQ;Guiguemde,WArmand;Barnett,DavidS;Maron,MaximI;Min,Jaeki;Connelly,MicheleC;Suryadevara,PraveenKumar;Guy,RKiplin;Williamson,KimC
• 通讯作者: Williamson,KimC