气候变化领域集成服务门户(CCPortal): Orthosteric–allosteric dual inhibitors of PfHT1 as selective antimalarial agents

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DOI	10.1073/pnas.2017749118
	Orthosteric–allosteric dual inhibitors of PfHT1 as selective antimalarial agents
	Huang J.; Yuan Y.; Zhao N.; Pu D.; Tang Q.; Zhang S.; Luo S.; Yang X.; Wang N.; Xiao Y.; Zhang T.; Liu Z.; Sakata-Kato T.; Jiang X.; Kato N.; Yan N.; Yin H.
发表日期	2021
ISSN	00278424
卷号	118 期号:3
英文摘要	Artemisinin-resistant malaria parasites have emerged and have been spreading, posing a significant public health challenge. Antimalarial drugs with novel mechanisms of action are therefore urgently needed. In this report, we exploit a “selective starvation” strategy by inhibiting Plasmodium falciparum hexose transporter 1 (PfHT1), the sole hexose transporter in P. falciparum, over human glucose transporter 1 (hGLUT1), providing an alternative approach to fight against multidrug-resistant malaria parasites. The crystal structure of hGLUT3, which shares 80% sequence similarity with hGLUT1, was resolved in complex with C3361, a moderate PfHT1-specific inhibitor, at 2.3-Å resolution. Structural comparison between the present hGLUT3-C3361 and our previously reported PfHT1-C3361 confirmed the unique inhibitor binding-induced pocket in PfHT1. We then designed small molecules to simultaneously block the orthosteric and allosteric pockets of PfHT1. Through extensive structure–activity relationship studies, the TH-PF series was identified to selectively inhibit PfHT1 over hGLUT1 and potent against multiple strains of the blood-stage P. falciparum. Our findings shed light on the next-generation chemotherapeutics with a paradigm-shifting structure-based design strategy to simultaneously target the orthosteric and allosteric sites of a transporter. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Hexose transporter \| antimalarial \| resistance \| structure-based drug design \| simultaneous orthosteric–allosteric inhibition
语种	英语
scopus关键词	antimalarial agent; compound 3361; dihydroartemisinin; glucose derivative; glucose transporter 1; glucose transporter 3; mefloquine; quinine; th pf 01; th pf 02; th pf 03; unclassified drug; antimalarial activity; antimalarial drug resistance; antiplasmodial activity; Article; blood; competitive inhibition; complex formation; computer model; computer simulation; controlled study; crystal structure; drug binding site; drug cytotoxicity; drug design; drug identification; drug potency; drug protein binding; drug selectivity; drug targeting; human; human cell; multidrug resistance; nonhuman; Plasmodium falciparum; priority journal; protein structure; sequence homology; structure activity relation
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180960
作者单位	Key Laboratory of Bioorganic Phosphorous Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China; Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing, 100084, China; State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, China; Global Health Drug Discovery Institute, Beijing, 100192, China; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, United States
推荐引用方式 GB/T 7714	Huang J.,Yuan Y.,Zhao N.,等. Orthosteric–allosteric dual inhibitors of PfHT1 as selective antimalarial agents[J],2021,118(3).
APA	Huang J..,Yuan Y..,Zhao N..,Pu D..,Tang Q..,...&Yin H..(2021).Orthosteric–allosteric dual inhibitors of PfHT1 as selective antimalarial agents.Proceedings of the National Academy of Sciences of the United States of America,118(3).
MLA	Huang J.,et al."Orthosteric–allosteric dual inhibitors of PfHT1 as selective antimalarial agents".Proceedings of the National Academy of Sciences of the United States of America 118.3(2021).