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

Jiang, Xin; Yuan, Yunbin; Huang, Jian; Zhang, Shuo; Luo, Shuchen; Wang, Nan; Pu, De-Bing; Zhao, Na; Tang, Qingxuan; Hirata, Kunio; Yang, Xikang; Jiao, Yaqing; Sakata‐Kato, Tomoyo; Wu, Jiawei; Yan, Chuangye; Kato, Nobutaka; Yin, Hang; Yan, Nieng

doi:10.1016/j.cell.2020.08.015

Cited by 56 publications

(104 citation statements)

References 68 publications

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“…Recently, we reported the structures of PfHT1 in complex with D-glucose and C3361 at resolution of 2.6 Å and 3.7 Å, respectively (18). Structural comparison between PfHT1 and hGLUT1 shows that residues around their glucose binding site are nearly identical ( Figure 1B/1C/S1).…”

Section: Inhibitor Binding-induced Pocket Unique To Pfht1mentioning

confidence: 94%

“…The tail of C3361 points to the interface between TM2 and TM11 ( Figure 2C). In the occluded structure of C3361-bound PfHT1 (18), the tail projects into the central cavity ( Figure 2D). These structural differences suggest that PfHT1 possesses unique intra-domain flexibility that may be exploited for designing selective inhibitors that target the allosteric site of PfHT1 without inhibiting GLUTs.…”

Section: Inhibitor Binding-induced Pocket Unique To Pfht1mentioning

confidence: 99%

“…Firstly, we examined different tail groups with various sizes to fit the allosteric pocket. Among them, the bicyclic rings, such as the naphthyl (2b) (18), quinolinyl (2h, 2i) (18), and biphenyl (2d) rings, enhanced the potency, whereas smaller (2a, 2f, 2g) or larger (2n, 2p) rings lowered the potency. Different positions of the linkers have been explored, suggesting that a particular orientation is desired presumably to fit well with the connecting channel (2b vs. 2c, 2d vs. 2e, 2h vs. 2m).…”

Section: S2)mentioning

confidence: 99%

“…Comparing the structures of PfHT1 (18,19) and hGLUT1 (20), we identified an additional pocket adjacent to the substrate-binding site. This discovery led to a hypothesis that another pharmacophore tethered to the carbohydrate core might render selective inhibitors for PfHT1.…”

Section: Introductionmentioning

confidence: 97%

“…The feasibility of this approach would depend on the successful development of selective PfHT1 inhibitors that do not affect the activities of human hexose transporter orthologs (e.g., hGLUT1). Previously, Compound 3361 (C3361) (16), a glucose analog, has been described to moderately inhibit PfHT1 and suppress the growth of the blood-stage parasites in vitro (17,18).…”

Section: Introductionmentioning

confidence: 99%

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Orthosteric-allosteric dual inhibitors of PfHT1 as selective anti-malarial agents

Huang

Yuan

Zhao

et al. 2020

Preprint

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Artemisinin-resistant malaria parasites have emerged and been spreading, posing a significant public health challenge. Anti-malarial drugs with novel mechanisms of action are therefore urgently needed. In this report, we exploit a “selective starvation” strategy by selectively inhibiting Plasmodium falciparum hexose transporter 1 (PfHT1), the sole hexose transporter in Plasmodium falciparum, over human glucose transporter 1 (hGLUT1), providing an alternative approach to fight against multidrug-resistant malaria parasites. Comparison of the crystal structures of human GLUT3 and PfHT1 bound to C3361, a PfHT1-specific moderate inhibitor, revealed an inhibitor binding-induced pocket that presented a promising druggable site. We thereby designed small-molecules to simultaneously block the orthosteric and allosteric pockets of PfHT1. Through extensive structure-activity relationship (SAR) studies, the TH-PF series was identified to selectively inhibit PfHT1 over GLUT1 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 targeting the orthosteric and allosteric sites of a transporter.Significance statementBlocking sugar uptake in P. falciparum by selectively inhibiting the hexose transporter PfHT1 kills the blood-stage parasites without affecting the host cells, indicating PfHT1 as a promising therapeutic target. Here, we report the development of novel small-molecule inhibitors that are selectively potent to the malaria parasites over human cell lines by simultaneously targeting the orthosteric and the allosteric binding sites of PfHT1. Our findings established the basis for the rational design of next-generation anti-malarial drugs.

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Section: Inhibitor Binding-induced Pocket Unique To Pfht1mentioning

confidence: 94%

Section: Inhibitor Binding-induced Pocket Unique To Pfht1mentioning

confidence: 99%

Section: S2)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Orthosteric-allosteric dual inhibitors of PfHT1 as selective anti-malarial agents

Huang

Yuan

Zhao

et al. 2020

Preprint

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Development of Mitochondria Targeting AIE‐Active Cyclometalated Iridium Complexes as Potent Antimalarial Agents

Kumari

Gupta

Sah

et al. 2022

Adv Healthcare Materials

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The emergence of resistance to conventional antimalarial treatments remains a major cause for concern. New drugs that target the distinct development stages of Plasmodium parasites are required to address this risk. Herein, water‐soluble aggregation‐induced emission active cyclometalated iridium(III) polypyridyl complexes (Ir1–Ir12) are developed for the elimination of malaria parasites. Remarkably, these complexes show potent antimalarial activity in low nanomolar range against 3D7 (chloroquine and artemisinin sensitive strain), RKL9 (chloroquine resistant strain), and R539T (artemisinin resistant strains) strains of Plasmodium falciparum with faster killing rate of malaria parasites. Concomitantly, these complexes exhibit efficient in vivo antimalarial activity against both the asexual and gametocyte stages of Plasmodium berghei malaria parasite, suggesting promising transmission‐blocking potential. The complexes tend to localize into mitochondria of P. falciparum determined by image and cell‐based assay. The mechanistic studies reveal that these complexes exert their antimalarial activity by increasing reactive oxygen species levels and disrupting its mitochondrial membrane potential. Furthermore, the mitochondrial‐dependent antimalarial activity of these complexes is confirmed in yeast model. Thus, this study for the first time highlights the potential role of targeting P. falciparum mitochondria by iridium complexes in discovering and developing the next‐generation antimalarial agents for treating multidrug resistant malaria parasites.

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Nontargeted metabolomics integrated with¹H NMR and LC–Q‐TOF–MS/MS methods to depict a more comprehensive metabolic profile in response to chrysosplenetin and artemisinin co‐treatment against artemisinin‐sensitive and ‐resistantPlasmodium bergheiK173

Wang

Tian

Chen

et al. 2022

Biomedical Chromatography

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Our previous work revealed mutual and specific metabolites/pathways in artemisinin‐sensitive and ‐resistant Plasmodium berghei K173‐infected mice. In this study, we further investigated whether chrysosplenetin, a candidate chemical to prevent artemisinin resistance, can regulate these metabolites/pathways by integrating nontargeted metabolomics with 1H NMR and LC–Q‐TOF–MS/MS spectrum. The nuclear magnetic resonance method generated specifically altered metabolites in response to co‐treatment with chrysosplenetin, including: the products of glycolysis such as glucose, pyruvate, lactate and alanine; taurine, closely associated with liver injury; arginine and proline as essential amino acids for parasites; TMAO, a biomarker for dysbacteriosis and renal function; and tyrosine, which is used to generate levodopa and dopamine and may improve the torpor state of mice. Importantly, we noticed that chrysosplenetin might depress the activated glycolysis induced by sensitive parasites, but oppositely promoted the inhibited glycolysis to generate more lactate, which suppresses the proliferation of resistant parasites. Moreover, chrysosplentin possibly disturbs the heme biosynthetic pathway in mitochondria. The MS method yielded changed coenzyme A, phosphatidylcholine and ceramides, closely related to mitochondria β‐oxidation, cell proliferation, differentiation and apoptosis. These two means shared no overlapped metabolites and formed a more broader metabolic map to study the potential mechanisms of chrysosplenetin as a promising artemisinin resistance inhibitor.

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

Cited by 56 publications

References 68 publications

Orthosteric-allosteric dual inhibitors of PfHT1 as selective anti-malarial agents

Orthosteric-allosteric dual inhibitors of PfHT1 as selective anti-malarial agents

Development of Mitochondria Targeting AIE‐Active Cyclometalated Iridium Complexes as Potent Antimalarial Agents

Nontargeted metabolomics integrated with¹H NMR and LC–Q‐TOF–MS/MS methods to depict a more comprehensive metabolic profile in response to chrysosplenetin and artemisinin co‐treatment against artemisinin‐sensitive and ‐resistantPlasmodium bergheiK173

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

Cited by 56 publications

References 68 publications

Orthosteric-allosteric dual inhibitors of PfHT1 as selective anti-malarial agents

Orthosteric-allosteric dual inhibitors of PfHT1 as selective anti-malarial agents

Development of Mitochondria Targeting AIE‐Active Cyclometalated Iridium Complexes as Potent Antimalarial Agents

Nontargeted metabolomics integrated with1H NMR and LC–Q‐TOF–MS/MS methods to depict a more comprehensive metabolic profile in response to chrysosplenetin and artemisinin co‐treatment against artemisinin‐sensitive and ‐resistantPlasmodium bergheiK173

Contact Info

Product

Resources

About

Nontargeted metabolomics integrated with¹H NMR and LC–Q‐TOF–MS/MS methods to depict a more comprehensive metabolic profile in response to chrysosplenetin and artemisinin co‐treatment against artemisinin‐sensitive and ‐resistantPlasmodium bergheiK173