Research Highlights: Cutting the Energy Source of the Malaria Parasite Plasmodium

Malaria parasites (purple) infect hosts’ red blood cells (pink, with mouse cells shown). JOSEPH TAKAHASHI LAB/UT SOUTHWESTERN MEDICAL CENTER/HHMI

Original Authors: 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

  • Malaria is a mosquito-borne disease caused by a parasite.
  • People with malaria often experience fever, chills, and flu-like illness.
  • Malaria is caused by single-celled microorganisms of the Plasmodium group.
  • Plasmodium species rely on glucose for energy supply during blood stage.
  • Cutting the glucose uptake is a potential strategy for the development of antimalarial drugs.
  • Plasmodium has a protein that transports glucose, and this protein is known to be essential for parasite growth and survival.
  • In another study, compound 3361 (C3361) has been described to moderately inhibits this glucose transporter protein and suppresses the growth of the blood-stage parasites.
  • This study present the crystal structures of the glucose transporter protein in complex with D-glucose and with the selective inhibitor C3361.
  • Although both structures were blocked, binding of C3361 causes marked rearrangements that result in an additional pocket.
  • This inhibitor-binding-induced pocket presents an opportunity for the rational design of the glucose transporter protein inhibitors.
  • Among the designed C3361 derivatives, several exhibited improved inhibition of glucose transporter protein and cellular potency against the parasite with excellent selectivity to human GLUT1.
  • GLUT1 facilitates the transport of glucose across the plasma membranes of mammalian cells.
  • The findings serve as a proof of concept for the development of the next-generation antimalarial chemotherapeutics by simultaneously targeting the primary binding site and allosteric sites of the glucose transporter protein.

Source:

https://doi.org/10.1016/j.cell.2020.08.015

https://www.cdc.gov/parasites/malaria/index.html

“Malaria Fact sheet N°94”WHO. March 2014. Archived from the original on 3 September 2014. Retrieved 28 August 2014.

https://pubmed.ncbi.nlm.nih.gov/26248369/

https://www.biorxiv.org/content/10.1101/2020.08.25.260232v1.full

Olson AL, Pessin JE (1996). “Structure, function, and regulation of the mammalian facilitative glucose transporter gene family”. Annual Review of Nutrition16: 235–56. doi:10.1146/annurev.nu.16.070196.001315PMID 8839927.


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