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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...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2021
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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. |
format | Online Article Text |
id | pubmed-7826358 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
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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