2. Academic Validation
  3. Structural Basis for Blocking Sugar Uptake into the Malaria Parasite Plasmodium falciparum

Structural Basis for Blocking Sugar Uptake into the Malaria Parasite Plasmodium falciparum

  • Cell. 2020 Oct 1;183(1):258-268.e12. doi: 10.1016/j.cell.2020.08.015.
Xin Jiang 1,  Yafei Yuan 2,  Jian Huang 3,  Shuo Zhang 1,  Shuchen Luo 3,  Nan Wang 1,  Debing Pu 4,  Na Zhao 5,  Qingxuan Tang 4,  Kunio Hirata 6,  Xikang Yang 3,  Yaqing Jiao 5,  Tomoyo Sakata-Kato 5,  Jia-Wei Wu 7,  Chuangye Yan 1,  Nobutaka Kato 5,  Hang Yin 8,  Nieng Yan 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Membrane Biology, Tsinghua University, Beijing 100084, China; Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China; School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 2 State Key Laboratory of Membrane Biology, Tsinghua University, Beijing 100084, China; Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China; School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 3 Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China; Department of Chemistry, Tsinghua University, Beijing 100084, China.
  • 4 Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China; School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.
  • 5 Global Health Drug Discovery Institute, Zhongguancun Dongsheng International Science Park, 1 North Yongtaizhuang Road, Beijing 100192, China.
  • 6 Advanced Photon Technology Division, Research Infrastructure Group, SR Life Science Instrumentation Unit, RIKEN/SPring-8 Center, Hyogo 679-5148, Japan.
  • 7 Institute of Molecular Enzymology, Soochow University, Suzhou, Jiangsu 215123, China.
  • 8 Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China; School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China. Electronic address: [email protected].
  • 9 State Key Laboratory of Membrane Biology, Tsinghua University, Beijing 100084, China; Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China; School of Life Sciences, Tsinghua University, Beijing 100084, China. Electronic address: [email protected].
PMID: 32860739 DOI: 10.1016/j.cell.2020.08.015
Abstract

Plasmodium species, the causative agent of malaria, rely on glucose for energy supply during blood stage. Inhibition of glucose uptake thus represents a potential strategy for the development of antimalarial drugs. Here, we present the crystal structures of PfHT1, the sole hexose transporter in the genome of Plasmodium species, at resolutions of 2.6 Å in complex with D-glucose and 3.7 Å with a moderately selective inhibitor, C3361. Although both structures exhibit occluded conformations, binding of C3361 induces marked rearrangements that result in an additional pocket. This inhibitor-binding-induced pocket presents an opportunity for the rational design of PfHT1-specific inhibitors. Among our designed C3361 derivatives, several exhibited improved inhibition of PfHT1 and cellular potency against P. falciparum, with excellent selectivity to human GLUT1. These findings serve as a proof of concept for the development of the next-generation antimalarial chemotherapeutics by simultaneously targeting the orthosteric and allosteric sites of PfHT1.

Keywords

PfHT1; Plasmodium falciparum; antimalarial; crystal structure; glucose transporter; hexose transporter; inhibitor-binding-induced pocket; malaria parasite; orthosteric and allosteric dual inhibition; structure-facilitated drug discovery.

Figures
Products