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摘要 : 近日,国际学术权威刊物自然出版集团《Nature》杂志上在线发表了美国诺华研究基金会基因组学研究所的Frantisek Supek研究员的一篇研究论文,研究报道了瞄准三种热带病的新药。

 近日,国际学术权威刊物自然出版集团《Nature》杂志上在线发表了美国诺华研究基金会基因组学研究所的Frantisek Supek研究员的一篇研究论文,研究报道了瞄准三种热带病的新药。查加斯病、利什曼病和昏睡病影响着2000万人,分别由动质体寄生虫克氏锥虫(Trypanosoma cruzi)、利什曼原虫(Leishmania spp.)和布氏锥虫(Trypanosoma brucei spp.)引起。作者采用筛选方法,寻找可治疗全部三者的新保守分子靶点和广谱药物,发现一种动质体蛋白酶体选择性抑制剂(GNF6702)最为有效。它在体内效果很好,可以清除这三种疾病的小鼠模型体内的寄生虫。GNF6702是一种特定于动质体蛋白酶体的非竞争性抑制剂,在小鼠中具有较高的耐受性。这些结果突显了开发一种药物、治疗上述三种被忽视疾病的可能性。


Proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness


Chagas disease, leishmaniasis and sleeping sickness affect 20 million people worldwide and lead to more than 50,000 deaths annually1. The diseases are caused by infection with the kinetoplastid parasites Trypanosoma cruzi, Leishmania spp. and Trypanosoma brucei spp., respectively. These parasites have similar biology and genomic sequence, suggesting that all three diseases could be cured with drugs that modulate the activity of a conserved parasite target2. However, no such molecular targets or broad spectrum drugs have been identified to date. Here we describe a selecive inhibitor of the kinetoplastid proteasome (GNF6702) with unprecedented in vivo efficacy, which cleared parasites from mice in all three models of infection. GNF6702 inhibits the kinetoplastid proteasome through a non-competitive mechanism, does not inhibit the mammalian proteasome or growth of mammalian cells, and is well-tolerated in mice. Our data provide genetic and chemical validation of the parasite proteasome as a promising therapeutic target for treatment of kinetoplastid infections, and underscore the possibility of developing a single class of drugs for these neglected diseases.

来源: Nature 浏览次数:1


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