Orthosteric–allosteric dual inhibitors of PfHT1 as selective antimalarial agents

Jian Huang, Yafei Yuan, Na Zhao, Debing Pu, Qingxuan Tang, Shuo Zhang, Shuchen Luo, Xikang Yang, Nan Wang, Yu Xiao, Tuan Zhang, Zhuoyi Liu, Tomoyo Sakata-Kato, Xin Jiang, Nobutaka Kato, Nieng Yan, Hang Yin

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


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.

Original languageEnglish (US)
Article numbere2017749118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number3
StatePublished - Jan 19 2021

All Science Journal Classification (ASJC) codes

  • General


  • Hexose transporter | antimalarial | resistance | structure-based drug design | simultaneous orthosteric–allosteric inhibition


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