Sun Wei, Huang Xiuli, Li Hao, Tawa Gregory, Fisher Ethan, Tanaka Takeshi Q, Shinn Paul, Huang Wenwei, Williamson Kim C, Zheng Wei
National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda, MD, 20892, USA.
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
Malar J. 2017 Apr 13;16(1):147. doi: 10.1186/s12936-017-1805-0.
Blocking malaria transmission is an important step in eradicating malaria. In the field, transmission requires the production of sexual stage Plasmodium parasites, called gametocytes, which are not effectively killed by the commonly used anti-malarials allowing individuals to remain infectious after clearance of asexual parasites.
To identify new gametocytocidal compounds, a library of 45,056 compounds with diverse structures was screened using a high throughput gametocyte viability assay. The characteristics of active hits were further evaluated against asexual stage parasites in a growth inhibition assay. Their cytotoxicity were tested against mammalian cells in a cytotoxicity assay. The chemical scaffold similarity of active hits were studied using scaffold cluster analysis.
A set of 23 compounds were identified and further confirmed for their activity against gametocytes. All the 23 confirmed compounds possess dual-activities against both gametocytes responsible for human to mosquito transmission and asexual parasites that cause the clinical symptoms. Three of these compounds were fourfold more active against gametocytes than asexual parasites. Further cheminformatic analysis revealed three sets of novel scaffolds, including highly selective 4-1H-pyrazol-5-yl piperidine analogs.
This study revealed important new structural scaffolds that can be used as starting points for dual activity anti-malarial drug development.
阻断疟疾传播是根除疟疾的重要一步。在野外，疟疾传播需要产生有性阶段的疟原虫，即配子体，常用的抗疟药物无法有效杀死这些配子体，这使得个体在无性寄生虫被清除后仍具传染性。
为了鉴定新的杀配子体化合物，使用高通量配子体活力测定法对一个包含45,056种结构各异的化合物文库进行了筛选。在生长抑制试验中，针对无性阶段寄生虫进一步评估活性命中物的特性。在细胞毒性试验中测试它们对哺乳动物细胞的细胞毒性。使用支架聚类分析研究活性命中物的化学支架相似性。
鉴定出一组23种化合物，并进一步确认了它们对配子体的活性。所有这23种经确认的化合物对负责人类向蚊子传播的配子体和引起临床症状的无性寄生虫均具有双重活性。其中三种化合物对配子体的活性比对无性寄生虫的活性高四倍。进一步的化学信息学分析揭示了三组新型支架，包括高度选择性的4-1H-吡唑-5-基哌啶类似物。
本研究揭示了重要的新结构支架，可作为开发双重活性抗疟药物的起点。
