2. Academic Validation
  3. Orthosteric-allosteric dual inhibitors of PfHT1 as selective antimalarial agents

Orthosteric-allosteric dual inhibitors of PfHT1 as selective antimalarial agents

  • Proc Natl Acad Sci U S A. 2021 Jan 19;118(3):e2017749118. doi: 10.1073/pnas.2017749118.
Jian Huang 1 2,  Yafei Yuan 2 3,  Na Zhao 4,  Debing Pu 1 2,  Qingxuan Tang 1 2,  Shuo Zhang 2 3,  Shuchen Luo 1 2,  Xikang Yang 1 2,  Nan Wang 2 3,  Yu Xiao 1 2,  Tuan Zhang 1 2,  Zhuoyi Liu 1 2,  Tomoyo Sakata-Kato 4,  Xin Jiang 5 3,  Nobutaka Kato 6,  Nieng Yan 5 3,  Hang Yin 7 2
Affiliations

Affiliations

  • 1 Key Laboratory of Bioorganic Phosphorous Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, School of Pharmaceutical Sciences, Tsinghua University,100084 Beijing, China.
  • 2 Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, 100084 Beijing, China.
  • 3 State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, 100084 Beijing, China.
  • 4 Global Health Drug Discovery Institute, 100192 Beijing, China.
  • 5 Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, 100084 Beijing, China; yin_hang@tsinghua.edu.cn nyan@princeton.edu nobutaka.kato@ghddi.org xin-jiang12@tsinghua.org.cn.
  • 6 Global Health Drug Discovery Institute, 100192 Beijing, China yin_hang@tsinghua.edu.cn nyan@princeton.edu nobutaka.kato@ghddi.org xin-jiang12@tsinghua.org.cn.
  • 7 Key Laboratory of Bioorganic Phosphorous Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, School of Pharmaceutical Sciences, Tsinghua University,100084 Beijing, China; yin_hang@tsinghua.edu.cn nyan@princeton.edu nobutaka.kato@ghddi.org xin-jiang12@tsinghua.org.cn.
PMID: 33402433 DOI: 10.1073/pnas.2017749118
Abstract

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.

Keywords

antimalarial; hexose transporter; resistance; simultaneous orthosteric–allosteric inhibition; structure-based drug design.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-17656
    PfHT1/PbHT1 Inhibitor