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Hexahydroquinolines are antimalarial candidates with potent blood-stage and transmission-blocking activity.
Nature Microbiology ( IF 28.3 ) Pub Date : 2017-Oct-01 , DOI: 10.1038/s41564-017-0007-4
Manu Vanaerschot , Leonardo Lucantoni , Tao Li , Jill M. Combrinck , Andrea Ruecker , T. R. Santha Kumar , Kelly Rubiano , Pedro E. Ferreira , Giulia Siciliano , Sonia Gulati , Philipp P. Henrich , Caroline L. Ng , James M. Murithi , Victoria C. Corey , Sandra Duffy , Ori J. Lieberman , M. Isabel Veiga , Robert E. Sinden , Pietro Alano , Michael J. Delves , Kim Lee Sim , Elizabeth A. Winzeler , Timothy J. Egan , Stephen L. Hoffman , Vicky M. Avery , David A. Fidock

Antimalarial compounds with dual therapeutic and transmission-blocking activity are desired as high-value partners for combination therapies. Here, we report the identification and characterization of hexahydroquinolines (HHQs) that show low nanomolar potency against both pathogenic and transmissible intra-erythrocytic forms of the malaria parasite Plasmodium falciparum. This activity translates into potent transmission-blocking potential, as shown by in vitro male gamete formation assays and reduced oocyst infection and prevalence in Anopheles mosquitoes. In vivo studies illustrated the ability of lead HHQs to suppress Plasmodium berghei blood-stage parasite proliferation. Resistance selection studies, confirmed by CRISPR-Cas9-based gene editing, identified the digestive vacuole membrane-spanning transporter PfMDR1 (P. falciparum multidrug resistance gene-1) as a determinant of parasite resistance to HHQs. Haemoglobin and haem fractionation assays suggest a mode of action that results in reduced haemozoin levels and might involve inhibition of host haemoglobin uptake into intra-erythrocytic parasites. Furthermore, parasites resistant to HHQs displayed increased susceptibility to several first-line antimalarial drugs, including lumefantrine, confirming that HHQs have a different mode of action to other antimalarials drugs for which PfMDR1 is known to confer resistance. This work evokes therapeutic strategies that combine opposing selective pressures on this parasite transporter as an approach to countering the emergence and transmission of multidrug-resistant P. falciparum malaria.

中文翻译:

六氢喹啉是抗疟疾的候选药物,具有有效的血液阶段和阻断传输的活性。

具有双重治疗和传递阻断活性的抗疟化合物被期望作为组合疗法的高价值伙伴。在这里,我们报告六氢喹啉(HHQs)的鉴定和表征,该六氢喹啉对疟原虫恶性疟原虫的致病性和可传播性红细胞内形式均表现出低纳摩尔浓度。如体外雄性配子形成试验所示,这种活性可转化为有效的阻断传导的潜能,可减少按蚊的卵囊感染和患病率。体内研究表明铅HHQs抑制伯氏疟原虫血液阶段寄生虫增殖的能力。通过基于CRISPR-Cas9的基因编辑证实的抗性选择研究确定了消化液泡跨膜转运蛋白PfMDR1(P. 恶性疟原虫多药抗性基因-1)作为对HHQs的寄生虫抗性的决定因素。血红蛋白和血红素分级测定表明了一种作用方式,可导致血红素水平降低,并可能涉及抑制宿主血红蛋白摄取到红细胞内的寄生虫中。此外,对HHQs产生抗药性的寄生虫对几种第一线抗疟药(包括lumefantrine)的敏感性增加,这证实HHQ与已知PfMDR1赋予抗药性的其他抗疟药具有不同的作用方式。这项工作唤起了治疗策略,该策略结合了该寄生虫转运蛋白上的相反选择性压力,以此作为抵抗多重耐药性恶性疟原虫疟疾出现和传播的方法。血红蛋白和血红素分级测定表明了一种作用方式,可导致血红素水平降低,并可能涉及抑制宿主血红蛋白摄取到红细胞内的寄生虫中。此外,对HHQs产生抗药性的寄生虫对几种第一线抗疟药(包括lumantantrine)的敏感性增强,证实了HHQ与已知PfMDR1赋予抗药性的其他抗疟药具有不同的作用方式。这项工作唤起了治疗策略,该策略结合了该寄生虫转运蛋白上的相反选择性压力,作为抵抗多重耐药性恶性疟原虫疟疾出现和传播的一种方法。血红蛋白和血红素分级测定表明了一种作用方式,可导致血红素水平降低,并可能涉及抑制宿主血红蛋白摄取到红细胞内的寄生虫中。此外,对HHQs产生抗药性的寄生虫对几种第一线抗疟药(包括lumefantrine)的敏感性增加,这证实HHQ与已知PfMDR1赋予抗药性的其他抗疟药具有不同的作用方式。这项工作唤起了治疗策略,该策略结合了该寄生虫转运蛋白上的相反选择性压力,作为抵抗多重耐药性恶性疟原虫疟疾出现和传播的一种方法。
更新日期:2017-08-14
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