Novel Minor Groove Binders Cure Animal African Trypanosomiasis in an in Vivo Mouse Model
Novel Minor Groove Binders Cure Animal African Trypanosomiasis in an in Vivo Mouse Model
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DOI：
10.1021/acs.jmedchem.8b01847
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发表时间：
2019-03-28
影响因子：
7.3
通讯作者：
Scott, Fraser J.
中科院分区：
文献类型：
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作者：
Giordani, Federica;Khalaf, Abedawn I.;Scott, Fraser J.
非洲动物锥虫病(AAT)是撒哈拉以南非洲的一个重大社会经济负担，因为它对牲畜健康造成了巨大影响。现有的治疗方法，包括那些基于微小沟槽粘合剂(MGB)的疗法，例如已经使用了几十年的二胺类药物，由于出现了抗药性寄生虫，现在在一些地方已经失去了疗效。因此，迫切需要新的化疗方法。在这里，我们描述了一类结构不同的微球，斯特拉斯克莱德微球(S-微球)，显示出良好的体外活性对主要致病微生物：锥虫和间日锥虫。我们还展示了一些这些化合物对感染弓形虫的小鼠的治疗作用。特别是，我们确定S-镁-234，化合物7，通过两次腹腔注射50 mg/kg来治疗。重要的是，我们证明了S-mGb与目前的二胺类药物没有交叉耐药性，也不是通过二胺类药物的转运蛋白内化的。本研究表明，S微球具有作为治疗AAT的新型药物的巨大潜力。
Animal African trypanosomiasis (AAT) is a significant socioeconomic burden for sub-Saharan Africa because of its huge impact on livestock health. Existing therapies including those based on minor groove binders (MGBs), such as the diamidines, which have been used for decades, have now lost efficacy in some places because of the emergence of resistant parasites. Consequently, the need for new chemotherapies is urgent. Here, we describe a structurally distinct class of MGBs, Strathclyde MGBs (S-MGBs), which display excellent in vitro activities against the principal causative organisms of AAT: Trypanosoma congolense, and Trypanosoma vivax. We also show the cure of T. congolense-infected mice by a number of these compounds. In particular, we identify S-MGB-234, compound 7, as curative by using two applications of 50 mg/kg intraperitoneally. Crucially, we demonstrate that S-MGBs do not show cross-resistance with the current diamidine drugs and are not internalized via the transporters used by diamidines. This study demonstrates that S-MGBs have significant potential as novel therapeutic agents for AAT.