Impact of Field Isolate Identified Nonsynonymous Single Nucleotide Polymorphisms on Plasmodium falciparum Equilibrative Nucleoside Transporter 1 Inhibitor Efficacy.
Impact of Field Isolate Identified Nonsynonymous Single Nucleotide Polymorphisms on Plasmodium falciparum Equilibrative Nucleoside Transporter 1 Inhibitor Efficacy.
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DOI：
10.1021/acsinfecdis.9b00203
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发表时间：
2020-02-14
影响因子：
5.3
通讯作者：
Akabas, Myles H.
中科院分区：
文献类型：
--
作者：
Sosa, Yvett;Egbo, Deborah;Akabas, Myles H.
恶性疟原虫引起最严重的疟疾，每年造成约50万人死亡。对当前抗疟疾治疗产生抗药性的恶性疟原虫正在传播。因此，开发新的抗疟疾药物势在必行。疟疾寄生虫是嘌呤营养缺乏症。它们依赖于从宿主红细胞通过平衡核苷转运体(Ents)输入的嘌呤。最近，恶性疟原虫ENT1抑制剂(PfENT1)在培养中抑制疟疾寄生虫的增殖已被确定为抗疟疾药物开发的有希望的起点。恶性疟原虫野外分离株基因组测序发现PfENT1基因存在非同义单核苷酸多态(SNPs)。在这里，我们评估了这些PfENT1 SNPs对嘌呤底物亲和力和抑制剂有效性的影响。我们在酿酒酵母中表达了每个PfENT1-SNP。使用表达PfENT1-SNP的酵母，通过放射性标记底物摄取抑制实验来表征PfENT1嘌呤底物的亲和力。在13个SNP中，有4个改变了对一种或多种嘌呤的亲和力，最高可达7倍。其中三个SNP使一组抑制剂的效力降低了多达7倍。一个SNP，Q284E，降低了所有六种抑制剂化学类型的效力。我们在含有PfENT1 SNPs的可用寄生虫菌株中测试了药物疗效。虽然表达PfENT1-SNP的酵母对PfENT1抑制剂的敏感性降低，但含有SNPs的寄生虫菌株对所有PfENT1抑制剂的抑制作用相似或更强。因此，携带PfENT1 SNPs的寄生虫菌株对这些PfENT1抑制剂不耐药。这支持PfENT1作为进一步开发新型抗疟疾药物的有希望的靶点。
Plasmodium falciparum causes the most severe form of malaria and causes approximately 500,000 deaths per year. P. falciparum parasites resistant to current anti-malarial treatments are spreading. Therefore, it is imperative to develop new anti-malarial drugs. Malaria parasites are purine auxotrophic. They rely on purine import from the host erythrocyte via Equilibrative Nucleoside Transporters (ENTs). Recently, inhibitors of the P. falciparum ENT1 (PfENT1) that inhibit proliferation of malaria parasites in culture have been identified as promising starting points for antimalarial drug development. Genome sequencing of P. falciparum field isolates has identified non-synonymous single nucleotide polymorphisms (SNPs) in the gene encoding PfENT1. Here we evaluate the impact of these PfENT1 SNPs on purine substrate affinity and inhibitor efficacy. We expressed each PfENT1-SNP in Saccharomyces cerevisiae. Using PfENT1-SNP-expressing yeast, we characterized the PfENT1 purine substrate affinity using radiolabeled substrate uptake inhibition experiments. Four of the 13 SNPs altered affinity for one or more purines by up to 7-fold. Three of the SNPs reduced the potency of a subset of the inhibitors by up to 7-fold. One SNP, Q284E, reduced the potency of all six inhibitor chemotypes. We tested drug efficacy in available parasite strains containing PfENT1 SNPs. While PfENT1-SNP-expressing yeast had decreased sensitivity to PfENT1 inhibitors, parasite strains containing SNPs showed similar or more potent inhibition of proliferation with all PfENT1 inhibitors. Thus, parasite strains bearing PfENT1 SNPs are not resistant to these PfENT1 inhibitors. This supports PfENT1 as a promising target for further development of novel antimalarial drugs.
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DOI：
10.1093/jac/dkp449
发表时间：
2010-03
期刊：
The Journal of antimicrobial chemotherapy
影响因子：
--
作者：
Nzila A;Mwai L
通讯作者：
Mwai L
影响因子：
4
作者：
Frame, I. J.;Deniskin, Roman;Akabas, Myles H.
通讯作者：
Akabas, Myles H.
影响因子：
5.7
作者：
Harrington, Susan E.;Ben-Tal, Nir
通讯作者：
Ben-Tal, Nir
影响因子：
3.5
作者：
Renne MF;de Kroon AIPM
通讯作者：
de Kroon AIPM
DOI：
10.1016/j.ijpddr.2015.11.003
发表时间：
2016-04-01
影响因子：
4
作者：
Deniskin, Roman;Frame, I. J.;Akabas, Myles H.
通讯作者：
Akabas, Myles H.