Thousands of chemical starting points for antimalarial lead identification
Thousands of chemical starting points for antimalarial lead identification
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DOI：
10.1038/nature09107
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发表时间：
2010-05-20
期刊：
影响因子：
64.8
通讯作者：
Garcia-Bustos, Jose F.
中科院分区：
文献类型：
--
作者：
Gamo, Francisco-Javier;Sanz, Laura M.;Garcia-Bustos, Jose F.
疟疾是由疟原虫属的原生动物引起的毁灭性感染。抗药性很普遍，自1996年以来，没有新的化学类抗疟药被引入临床实践，最近出现了对最新药物敏感性降低的寄生虫菌株。我们在葛兰素史克的化学库中筛选了近200万种化合物，以寻找恶性疟原虫的抑制剂，其中13，533种化合物被证实在2 μ M浓度下抑制寄生虫生长至少80%。超过8，000种还对多药耐药菌株Dd 2表现出强效活性。大多数（82%）化合物来自公司内部项目，是疟疾社区的新产品。使用历史检测数据的分析表明了几种新的抗疟作用机制，如抑制蛋白激酶和宿主-病原体相互作用相关靶标。化学结构和相关数据特此公布，以鼓励更多的药物先导鉴定工作和对这种疾病的进一步研究。
Malaria is a devastating infection caused by protozoa of the genus Plasmodium. Drug resistance is widespread, no new chemical class of antimalarials has been introduced into clinical practice since 1996 and there is a recent rise of parasite strains with reduced sensitivity to the newest drugs. We screened nearly 2 million compounds in GlaxoSmithKline's chemical library for inhibitors of P. falciparum, of which 13,533 were confirmed to inhibit parasite growth by at least 80% at 2 mu M concentration. More than 8,000 also showed potent activity against the multidrug resistant strain Dd2. Most (82%) compounds originate from internal company projects and are new to the malaria community. Analyses using historic assay data suggest several novel mechanisms of antimalarial action, such as inhibition of protein kinases and host-pathogen interaction related targets. Chemical structures and associated data are hereby made public to encourage additional drug lead identification efforts and further research into this disease.