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

Xin Jiang, Yafei Yuan, Jian Huang, Shuo Zhang, Shuchen Luo, Nan Wang, Debing Pu, Na Zhao, Qingxuan Tang, Kunio Hirata, Xikang Yang, Yaqing Jiao, Tomoyo Sakata-Kato, Jia Wei Wu, Chuangye Yan, Nobutaka Kato, Hang Yin, Nieng Yan

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)258-268.e12
JournalCell
Volume183
Issue number1
DOIs
StatePublished - Oct 1 2020

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Keywords

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

Fingerprint Dive into the research topics of 'Structural Basis for Blocking Sugar Uptake into the Malaria Parasite Plasmodium falciparum'. Together they form a unique fingerprint.

  • Cite this

    Jiang, X., Yuan, Y., Huang, J., Zhang, S., Luo, S., Wang, N., Pu, D., Zhao, N., Tang, Q., Hirata, K., Yang, X., Jiao, Y., Sakata-Kato, T., Wu, J. W., Yan, C., Kato, N., Yin, H., & Yan, N. (2020). Structural Basis for Blocking Sugar Uptake into the Malaria Parasite Plasmodium falciparum. Cell, 183(1), 258-268.e12. https://doi.org/10.1016/j.cell.2020.08.015