NCATS Malaria Active Collection

NCATS 疟疾活性系列

• 批准号: 10691135
• 负责人: Alexey Zakharov
• 金额: $ 14.62万
• 依托单位: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10691135
• 关键词: Antimalarials; Artemisinins; Beds; Biology; Blood; Chemicals; Chloroquine; Clinical Treatment; Co-Rax; Collection; Combined Modality Therapy; Country; Diagnostic tests; Dose; Drug resistance; Effectiveness; Erythrocytes; Genetic; Genetic Crosses; Genomic approach; High Prevalence; Incidence; Insecticides; Life Cycle Stages; Malaria; Mediating; Molecular Target; Morbidity - disease rate; Mutate; Mutation; National Center for Advancing Translational Sciences; Parasite resistance; Parasites; Pathway interactions; Pharmaceutical Preparations; Phenotype; Plasmodium; Plasmodium falciparum; Predisposition; Pyrimethamine; Rapid diagnostics; Residual state; Resistance; Resistance development; Treatment Failure; Variant; asexual; base; chemotherapeutic agent; drug action; genomic locus; high throughput screening; in vivo; insight; mortality; novel; novel drug combination; novel therapeutics; response; small molecule

The emergence and spread of resistance to current antimalarial therapies threatens to reverse gains made in reducing malaria related morbidity and mortality. Novel chemotherapeutic agents, along with increased insight into mechanisms of drug action and potential modes of resistance, are essential to counteract this threat. From over 500,000 small molecules screened against the asexual blood stage of Plasmodium falciparum in dose-response, we have assembled the NCATS Malaria Active Collection (NMAC). This collection of 1,339 compounds with potent activity against the asexual blood stage were used to profile the drug susceptibility response across the parasite life cycle, presenting a chemical biology snapshot of targetable pathways. In addition, using three Plasmodium genetic crosses, a chemical genomic approach was leveraged to gain insight into genetic loci modulating drug susceptibility. 204 compounds (15.2%) demonstrated significantly variant activity between the three parental lines (Dd2HB3, 91 compounds; 7G8GB4, 100 compounds; 803GB4, 42 compounds). Only four compounds were differentially active against all three comparisons. These include the antimalarials chloroquine and pyrimethamine, suggesting greater genetic complexity underlying drug response than previously observed.

对目前抗疟疗法的抗药性的出现和蔓延，有可能使在降低疟疾相关发病率和死亡率方面取得的成果发生逆转。新的化疗药物，沿着对药物作用机制和潜在耐药模式的深入了解，对于应对这一威胁至关重要。从超过500，000个针对恶性疟原虫无性血液阶段的剂量反应筛选的小分子中，我们组装了NCATS疟疾活性收集（NMAC）。 这些对无性血液阶段具有强效活性的1，339种化合物被用于描述整个寄生虫生命周期的药物敏感性反应，提供了可靶向途径的化学生物学快照。此外，使用三种疟原虫遗传杂交，利用化学基因组方法来深入了解调节药物敏感性的遗传位点。204个化合物（15.2%）在三个亲本系之间表现出显著的变异活性（Dd 2 HB 3，91个化合物; 7 G8 GB 4，100个化合物; 803 GB 4，42个化合物）。只有四种化合物对所有三种比较具有不同的活性。这些包括抗疟药氯喹和乙胺嘧啶，表明药物反应的遗传复杂性比以前观察到的要大。