@article{cc9ff2c87da1470abd2f3cd4a89e6ef1,
title = "Structural Basis for Blocking Sugar Uptake into the Malaria Parasite Plasmodium falciparum",
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 {\AA} in complex with D-glucose and 3.7 {\AA} 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",
author = "Xin Jiang and Yafei Yuan and Jian Huang and Shuo Zhang and Shuchen Luo and Nan Wang and Debing Pu and Na Zhao and Qingxuan Tang and Kunio Hirata and Xikang Yang and Yaqing Jiao and Tomoyo Sakata-Kato and Wu, {Jia Wei} and Chuangye Yan and Nobutaka Kato and Hang Yin and Nieng Yan",
note = "Funding Information: We thank Yigong Shi for critical discussions throughout this project. We thank Haipeng Gong for discussions on the computational simulations. We thank the X-ray Crystallography Platform of the Tsinghua University Technology Center for Protein Research for the crystallization facility. We thank Bo Sun at Shanghai Synchrotron Radiation Facility (SSRF) BL18U beamline for crystal screening. This work was supported by funds from the National Natural Science Foundation of China (projects 31630017 , 81861138009 , and 21825702 ). H.Y. acknowledges the Beijing Outstanding Young Scientist Program grant no. BJJWZYJH01201910003013 . We thank support from the Beijing Municipal Government and Bill & Melinda Gates Foundation to GHDDI . Funding Information: We thank Yigong Shi for critical discussions throughout this project. We thank Haipeng Gong for discussions on the computational simulations. We thank the X-ray Crystallography Platform of the Tsinghua University Technology Center for Protein Research for the crystallization facility. We thank Bo Sun at Shanghai Synchrotron Radiation Facility (SSRF) BL18U beamline for crystal screening. This work was supported by funds from the National Natural Science Foundation of China (projects 31630017, 81861138009, and 21825702). H.Y. acknowledges the Beijing Outstanding Young Scientist Program grant no. BJJWZYJH01201910003013. We thank support from the Beijing Municipal Government and Bill & Melinda Gates Foundation to GHDDI. N.Y. conceived the project. X.J. J.H. Y.Y. H.Y. and N.Y. designed all experiments. X.J. Y.Y. and S.Z. performed experiments related to protein generation, crystallization, and structural determination. X.J. Y.Y. S.Z. and N.W performed all biochemical assays. H.Y. and J.H. are responsible for the inhibitor development. J.H. and S.L. are responsible for computational simulations. J.H. D.P. Q.T. and X.Y. are responsible for chemical synthesis and characterizations. N.Z. Y.J. T.S.-K. and N.K. designed, executed, and analyzed parasitological and cytotoxicity experiments. X.J. K.H. and C.Y. contributed to structure determination. All authors analyzed the data. N.Y. H.Y. X.J. J.H. and Y.Y. prepared the manuscript. 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. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = oct,
day = "1",
doi = "10.1016/j.cell.2020.08.015",
language = "English (US)",
volume = "183",
pages = "258--268.e12",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "1",
}