A high throughput screen for next-generation leads targeting malaria parasite transmission
A high throughput screen for next-generation leads targeting malaria parasite transmission
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DOI：
10.1038/s41467-018-05777-2
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发表时间：
2018-09-18
影响因子：
16.6
通讯作者：
Baum, Jake
中科院分区：
文献类型：
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作者：
Delves, Michael J.;Miguel-Blanco, Celia;Baum, Jake
寄生虫对青蒿素耐药性的传播威胁到目前的一线抗疟疾疗法，突出表明需要具有替代作用方式的新药。由于只有0.2% -1%的无性寄生虫分化为有性的、具有传播能力的形式，因此针对这一自然瓶颈提供了阻断疾病传播和减轻抗性选择的切实途径。在这里，我们展示了一个高通量的配子发生筛选，针对类似于7万种化合物多样性文库，确定了17种靶向传播的药物样分子。Hit分子具有多种活性特征，包括男性特异性，双作用雄性-雌性和双无性-性，其中一种有希望的N-（（4-羟基铬-4基）甲基）磺胺支架在体外和体内具有亚微摩尔活性。针对疟疾寄生虫发育的性阶段开发具有作用模式的先导物提供了一个以前未开发的基础，可据此开发未来的治疗方法，能够防止寄生虫在人群中传播。
Spread of parasite resistance to artemisinin threatens current frontline antimalarial therapies, highlighting the need for new drugs with alternative modes of action. Since only 0.2-1% of asexual parasites differentiate into sexual, transmission-competent forms, targeting this natural bottleneck provides a tangible route to interrupt disease transmission and mitigate resistance selection. Here we present a high-throughput screen of gametogenesis against a similar to 70,000 compound diversity library, identifying seventeen drug-like molecules that target transmission. Hit molecules possess varied activity profiles including male-specific, dual acting male-female and dual-asexual-sexual, with one promising N-((4-hydroxychroman-4yl)methyl)-sulphonamide scaffold found to have sub-micromolar activity in vitro and in vivo efficacy. Development of leads with modes of action focussed on the sexual stages of malaria parasite development provide a previously unexplored base from which future therapeutics can be developed, capable of preventing parasite transmission through the population.