Dataset Information

Orthosteric-allosteric dual inhibitors of PfHT1 as selective antimalarial agents.

ABSTRACT: 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.

SUBMITTER: Huang J

PROVIDER: S-EPMC7826358 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Orthosteric-allosteric dual inhibitors of PfHT1 as selective antimalarial agents.

Huang Jian J Yuan Yafei Y Zhao Na N Pu Debing D Tang Qingxuan Q Zhang Shuo S Luo Shuchen S Yang Xikang X Wang Nan N Xiao Yu Y Zhang Tuan T Liu Zhuoyi Z Sakata-Kato Tomoyo T Jiang Xin X Kato Nobutaka N Yan Nieng N Yin Hang H

Proceedings of the National Academy of Sciences of the United States of America 20210101 3

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 <i>Plasmodium falciparum</i> hexose transporter 1 (PfHT1), the sole hexose transporter in <i>P. falciparum</i>, over human glucose transporter 1 (hGLUT1), providing an alternative approach to fight against multidrug-res ...[more]

PMID: 33402433

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Project description:The urokinase receptor (uPAR) is a GPI-anchored cell surface receptor that is at the center of an intricate network of protein-protein interactions. Its immediate binding partners are the serine proteinase urokinase (uPA), and vitronectin (VTN), a component of the extracellular matrix. uPA and VTN bind at distinct sites on uPAR to promote extracellular matrix degradation and integrin signaling, respectively. Here, we report the discovery of a new class of pyrrolone small-molecule inhibitors of the tight ?1 nM uPAR·uPA protein-protein interaction. These compounds were designed to bind to the uPA pocket on uPAR. The highest affinity compound, namely 7, displaced a fluorescently labeled ?-helical peptide (AE147-FAM) with an inhibition constant Ki of 0.7 ?M and inhibited the tight uPAR·uPAATF interaction with an IC50 of 18 ?M. Biophysical studies with surface plasmon resonance showed that VTN binding is highly dependent on uPA. This cooperative binding was confirmed as 7, which binds at the uPAR·uPA interface, also inhibited the distal VTN·uPAR interaction. In cell culture, 7 blocked the uPAR·uPA interaction in uPAR-expressing human embryonic kidney (HEK-293) cells and impaired cell adhesion to VTN, a process that is mediated by integrins. As a result, 7 inhibited integrin signaling in MDA-MB-231 cancer cells as evidenced by a decrease in focal adhesion kinase (FAK) phosphorylation and Rac1 GTPase activation. Consistent with these results, 7 blocked breast MDA-MB-231 cancer cell invasion with IC50 values similar to those observed in ELISA and surface plasmon resonance competition studies. Explicit-solvent molecular dynamics simulations show that the cooperativity between uPA and VTN is attributed to stabilization of uPAR motion by uPA. In addition, free energy calculations revealed that uPA stabilizes the VTNSMB·uPAR interaction through more favorable electrostatics and entropy. Disruption of the uPAR·VTNSMB interaction by 7 is consistent with the cooperative binding to uPAR by uPA and VTN. Interestingly, the VTNSMB·uPAR interaction was less favorable in the VTNSMB·uPAR·7 complex suggesting potential cooperativity between 7 and VTN. Compound 7 provides an excellent starting point for the development of more potent derivatives to explore uPAR biology.

Dataset Information

Orthosteric-allosteric dual inhibitors of PfHT1 as selective antimalarial agents.

Publications

Orthosteric-allosteric dual inhibitors of PfHT1 as selective antimalarial agents.

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