NCATS Malaria Active Collection

NCATS 疟疾活性系列

基本信息

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
项目类别：
财政年份：
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

项目摘要

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.

对当前抗疟疾疗法的抵抗力的出现和传播有可能在降低疟疾相关的发病率和死亡率方面取得的逆转。新型的化学治疗剂以及对药物作用机制和潜在耐药性机制的洞察力增加至关重要。从剂量反应中的疟原虫疟原虫的无性血液筛选的超过500,000个小分子中，我们组装了NCATS疟疾活性收集（NMAC）。该收集的1,339种对无性血液阶段有效活性的化合物用于介绍整个寄生虫生命周期的药物敏感性反应，并提供了可靶向途径的化学生物学快照。此外，使用三个疟原虫遗传十字，杠杆化了一种化学基因组方法，以深入了解遗传基因座调节药物易感性。 204种化合物（15.2％）表现出三个父母线（DD2HB3，91种化合物; 7g8gb4，100化合物; 803GB4，42种化合物）之间的显着变化活性。在所有三个比较中，只有四种化合物具有差异性活性。这些包括抗疟疾氯喹和嘧啶胺，表明与先前观察到的药物反应相比，遗传复杂性更大。