Structural Basis for Blocking Sugar Uptake into the Malaria Parasite Plasmodium falciparum - PubMed (original) (raw)

. 2020 Oct 1;183(1):258-268.e12.

doi: 10.1016/j.cell.2020.08.015. Epub 2020 Aug 28.

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

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

Xin Jiang et al. Cell. 2020.

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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.

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Conflict of interest statement

Declaration of Interests A patent application was filed. Applicant: Institution: Tsinghua University. Application number: PCT/CN2020/074258. Status of application: not yet published. Specific aspect of manuscript covered in patent application: crystal structure of PfHT1 in complex with C3361, the inhibitor-binding-induced pocket in C3361-bound structure, compounds HTI-1, and derivatives and their activities.

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