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.
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