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Orthosteric–allosteric dual inhibitors of PfHT1 as selective antimalarial agents

Artemisinin-resistant malaria parasites have emerged and have been spreading, posing a significant public health challenge. Antimalarial drugs with novel mechanisms of action are therefore urgently needed. In this report, we exploit a “selective starvation” strategy by inhibiting Plasmodium falcipar...

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Autores principales: Huang, Jian, Yuan, Yafei, Zhao, Na, Pu, Debing, Tang, Qingxuan, Zhang, Shuo, Luo, Shuchen, Yang, Xikang, Wang, Nan, Xiao, Yu, Zhang, Tuan, Liu, Zhuoyi, Sakata-Kato, Tomoyo, Jiang, Xin, Kato, Nobutaka, Yan, Nieng, Yin, Hang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826358/
https://www.ncbi.nlm.nih.gov/pubmed/33402433
http://dx.doi.org/10.1073/pnas.2017749118
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author Huang, Jian
Yuan, Yafei
Zhao, Na
Pu, Debing
Tang, Qingxuan
Zhang, Shuo
Luo, Shuchen
Yang, Xikang
Wang, Nan
Xiao, Yu
Zhang, Tuan
Liu, Zhuoyi
Sakata-Kato, Tomoyo
Jiang, Xin
Kato, Nobutaka
Yan, Nieng
Yin, Hang
author_facet Huang, Jian
Yuan, Yafei
Zhao, Na
Pu, Debing
Tang, Qingxuan
Zhang, Shuo
Luo, Shuchen
Yang, Xikang
Wang, Nan
Xiao, Yu
Zhang, Tuan
Liu, Zhuoyi
Sakata-Kato, Tomoyo
Jiang, Xin
Kato, Nobutaka
Yan, Nieng
Yin, Hang
author_sort Huang, Jian
collection PubMed
description Artemisinin-resistant malaria parasites have emerged and have been spreading, posing a significant public health challenge. Antimalarial drugs with novel mechanisms of action are therefore urgently needed. In this report, we exploit a “selective starvation” strategy by inhibiting Plasmodium falciparum hexose transporter 1 (PfHT1), the sole hexose transporter in P. falciparum, over human glucose transporter 1 (hGLUT1), providing an alternative approach to fight against multidrug-resistant malaria parasites. The crystal structure of hGLUT3, which shares 80% sequence similarity with hGLUT1, was resolved in complex with C3361, a moderate PfHT1-specific inhibitor, at 2.3-Å resolution. Structural comparison between the present hGLUT3-C3361 and our previously reported PfHT1-C3361 confirmed the unique inhibitor binding-induced pocket in PfHT1. We then designed small molecules to simultaneously block the orthosteric and allosteric pockets of PfHT1. Through extensive structure–activity relationship studies, the TH-PF series was identified to selectively inhibit PfHT1 over hGLUT1 and potent against multiple strains of the blood-stage P. falciparum. Our findings shed light on the next-generation chemotherapeutics with a paradigm-shifting structure-based design strategy to simultaneously target the orthosteric and allosteric sites of a transporter.
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spelling pubmed-78263582021-01-28 Orthosteric–allosteric dual inhibitors of PfHT1 as selective antimalarial agents Huang, Jian Yuan, Yafei Zhao, Na Pu, Debing Tang, Qingxuan Zhang, Shuo Luo, Shuchen Yang, Xikang Wang, Nan Xiao, Yu Zhang, Tuan Liu, Zhuoyi Sakata-Kato, Tomoyo Jiang, Xin Kato, Nobutaka Yan, Nieng Yin, Hang Proc Natl Acad Sci U S A Biological Sciences Artemisinin-resistant malaria parasites have emerged and have been spreading, posing a significant public health challenge. Antimalarial drugs with novel mechanisms of action are therefore urgently needed. In this report, we exploit a “selective starvation” strategy by inhibiting Plasmodium falciparum hexose transporter 1 (PfHT1), the sole hexose transporter in P. falciparum, over human glucose transporter 1 (hGLUT1), providing an alternative approach to fight against multidrug-resistant malaria parasites. The crystal structure of hGLUT3, which shares 80% sequence similarity with hGLUT1, was resolved in complex with C3361, a moderate PfHT1-specific inhibitor, at 2.3-Å resolution. Structural comparison between the present hGLUT3-C3361 and our previously reported PfHT1-C3361 confirmed the unique inhibitor binding-induced pocket in PfHT1. We then designed small molecules to simultaneously block the orthosteric and allosteric pockets of PfHT1. Through extensive structure–activity relationship studies, the TH-PF series was identified to selectively inhibit PfHT1 over hGLUT1 and potent against multiple strains of the blood-stage P. falciparum. Our findings shed light on the next-generation chemotherapeutics with a paradigm-shifting structure-based design strategy to simultaneously target the orthosteric and allosteric sites of a transporter. National Academy of Sciences 2021-01-19 2021-01-05 /pmc/articles/PMC7826358/ /pubmed/33402433 http://dx.doi.org/10.1073/pnas.2017749118 Text en Copyright © 2021 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Huang, Jian
Yuan, Yafei
Zhao, Na
Pu, Debing
Tang, Qingxuan
Zhang, Shuo
Luo, Shuchen
Yang, Xikang
Wang, Nan
Xiao, Yu
Zhang, Tuan
Liu, Zhuoyi
Sakata-Kato, Tomoyo
Jiang, Xin
Kato, Nobutaka
Yan, Nieng
Yin, Hang
Orthosteric–allosteric dual inhibitors of PfHT1 as selective antimalarial agents
title Orthosteric–allosteric dual inhibitors of PfHT1 as selective antimalarial agents
title_full Orthosteric–allosteric dual inhibitors of PfHT1 as selective antimalarial agents
title_fullStr Orthosteric–allosteric dual inhibitors of PfHT1 as selective antimalarial agents
title_full_unstemmed Orthosteric–allosteric dual inhibitors of PfHT1 as selective antimalarial agents
title_short Orthosteric–allosteric dual inhibitors of PfHT1 as selective antimalarial agents
title_sort orthosteric–allosteric dual inhibitors of pfht1 as selective antimalarial agents
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826358/
https://www.ncbi.nlm.nih.gov/pubmed/33402433
http://dx.doi.org/10.1073/pnas.2017749118
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