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) 分析最近发现的可在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) 通过筛选确定对配子体繁殖和传播至关重要的代谢途径具有已知靶点的药理活性抑制剂库。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。

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。

• 发表时间: 2015-03
• 影响因子: 4.9
• 作者: Tanaka, Takeshi Q;Guiguemde, W Armand;Barnett, David S;Maron, Maxim I;Min, Jaeki;Connelly, Michele C;Suryadevara, Praveen Kumar;Guy, R Kiplin;Williamson, Kim C
• 通讯作者: Williamson, Kim C

A quantitative high throughput assay for identifying gametocytocidal compounds.

用于鉴定杀配子细胞化合物的定量高通量测定。

• 发表时间: 2013-03
• 影响因子: 1.5
• 作者: Tanaka, Takeshi Q;Dehdashti, Seameen J;Nguyen, Dac;McKew, John C;Zheng, Wei;Williamson, Kim C
• 通讯作者: Williamson, Kim C

Chemical signatures and new drug targets for gametocytocidal drug development.

用于杀配子药物开发的化学特征和新药物靶点。

• 发表时间: 2014
• 影响因子: 4.6
• 作者: Sun, Wei;Tanaka, Takeshi Q;Magle, Crystal T;Huang, Wenwei;Southall, Noel;Huang, Ruili;Dehdashti, Seameen J;McKew, John C;Williamson, Kim C;Zheng, Wei
• 通讯作者: Zheng, Wei