Development of Glucose Transporter (GLUT) Inhibitors

Reckzeh, Elena S.; Waldmann, Herbert

doi:10.1002/ejoc.201901353

Cited by 34 publications

(31 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the other hand, pharmacological strategies such as the use of GLUT 1 inhibitors (GLUT-1i) aimed at inhibiting glucose transporters could be evaluated in the treatment of critically ill patients, since there is an increase in the expression of GLUTs in immune and non-immune cells in these patients. In fact, the use of glucose inhibitors as a therapeutic strategy in other infectious diseases (e.g., Zika virus or Human T cell Leukemia Virus infections) and in various types of cancer cells has been documented in vitro by other authors (Manel et al, 2003;Dominguez Rieg and Rieg, 2019;Lin et al, 2019;Reckzeh and Waldmann, 2020;Cao et al, 2021) but data are necessary in the context of the possible use of GLUT-1i as complementary therapy in severe COVID-19 infection.…”

Section: Therapeutic Strategiesmentioning

confidence: 99%

Changes in Glycolytic Pathway in SARS-COV 2 Infection and Their Importance in Understanding the Severity of COVID-19

et al. 2021

View full text Add to dashboard Cite

COVID-19 is an infectious disease caused by Coronavirus 2 (SARS-CoV-2) that may lead to a severe acute respiratory syndrome. Such syndrome is thought to be related, at least in part, to a dysregulation of the immune system which involves three main components: hyperactivity of the innate immune system; decreased production of type 1 Interferons (IFN) by SARS-CoV-2-infected cells, namely respiratory epithelial cells and macrophages; and decreased numbers of both CD4+ and particularly CD8+ T cells. Herein, we describe how excessive activation of the innate immune system and the need for viral replication in several cells of the infected organism promote significant alterations in cells’ energy metabolism (glucose metabolism), which may underlie the poor prognosis of the disease in severe situations. When activated, cells of the innate immune system reprogram their metabolism, and increase glucose uptake to ensure secretion of pro-inflammatory cytokines. Changes in glucose metabolism are also observed in pulmonary epithelial cells, contributing to dysregulation of cytokine synthesis and inflammation of the pulmonary epithelium. Controlling hyperglycolysis in critically ill patients may help to reduce the exaggerated production of pro-inflammatory cytokines and optimise the actions of the adaptive immune system. In this review, we suggest that the administration of non-toxic concentrations of 2-deoxy-D-glucose, the use of GLUT 1 inhibitors, of antioxidants such as vitamin C in high doses, as well as the administration of N-acetylcysteine in high doses, may be useful complementary therapeutic strategies for these patients, as suggested by some clinical trials and/ or reports. Overall, understanding changes in the glycolytic pathway associated with COVID-19 infection can help to find new forms of treatment for this disease.

show abstract

Section: Therapeutic Strategiesmentioning

confidence: 99%

Changes in Glycolytic Pathway in SARS-COV 2 Infection and Their Importance in Understanding the Severity of COVID-19

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Several compounds were discovered that effectively inhibit glucose uptake via GLUTs in cell lines 32 . Glupin and glutor, for example, are very potent inhibitors for GLUT1 and 3 or GLUT1-3, respectively; 2-deoxy-glucose uptake experiments with human cell lines revealed their high potency with IC 50 values in the nanomolar range 33 , 34 .…”

Section: Introductionmentioning

confidence: 99%

Identification of new GLUT2-selective inhibitors through in silico ligand screening and validation in eukaryotic expression systems

Schmidl

Ursu

Iancu

et al. 2021

Sci Rep

View full text Add to dashboard Cite

Glucose is an essential energy source for cells. In humans, its passive diffusion through the cell membrane is facilitated by members of the glucose transporter family (GLUT, SLC2 gene family). GLUT2 transports both glucose and fructose with low affinity and plays a critical role in glucose sensing mechanisms. Alterations in the function or expression of GLUT2 are involved in the Fanconi–Bickel syndrome, diabetes, and cancer. Distinguishing GLUT2 transport in tissues where other GLUTs coexist is challenging due to the low affinity of GLUT2 for glucose and fructose and the scarcity of GLUT-specific modulators. By combining in silico ligand screening of an inward-facing conformation model of GLUT2 and glucose uptake assays in a hexose transporter-deficient yeast strain, in which the GLUT1-5 can be expressed individually, we identified eleven new GLUT2 inhibitors (IC50 ranging from 0.61 to 19.3 µM). Among them, nine were GLUT2-selective, one inhibited GLUT1-4 (pan-Class I GLUT inhibitor), and another inhibited GLUT5 only. All these inhibitors dock to the substrate cavity periphery, close to the large cytosolic loop connecting the two transporter halves, outside the substrate-binding site. The GLUT2 inhibitors described here have various applications; GLUT2-specific inhibitors can serve as tools to examine the pathophysiological role of GLUT2 relative to other GLUTs, the pan-Class I GLUT inhibitor can block glucose entry in cancer cells, and the GLUT2/GLUT5 inhibitor can reduce the intestinal absorption of fructose to combat the harmful effects of a high-fructose diet.

show abstract

“…ALD A is one of the enzymes involved in glycolysis, and GLUT1 is a glycolysis-promoting protein. 27 , 28 These results demonstrated that Rox induces proliferation and glycolysis in primary cultured rat aorta VECs.…”

Section: Discussionmentioning

confidence: 73%

Roxarsone Promotes Glycolysis and Angiogenesis by Inducing Hypoxia-Inducible Factor-1α In Vitro and In Vivo

et al. 2021

View full text Add to dashboard Cite

Roxarsone (Rox) is an organic arsenic compound used as a feed additive to promote animal growth. The release of Rox into the environment poses risks to human health. Rox demonstrated tumor-promoting and proangiogenic effects in xenograft models. Increasing studies revealed the tight relationship among angiogenesis, carcinogenesis, tumorigenesis, and glycolysis. Glycolysis, via hypoxia-inducible factor-1α (HIF-1α), controls vascular endothelial cell (VEC) growth. To date, there has been no literature report on the effect of Rox on HIF-1α-dependent glycolysis. Herein, we report that Rox promoted glycolysis in rat VECs, as shown by the increased adenosine triphosphate production, the lactic acid release, the activity and content of aldolase (ALD), and the expression levels of ALD A and glucose transporter 1 (GLUT1). Rox also increased the cellular levels of HIF-1α. Treatment with the HIF-1α inhibitor YC-1 reversed Rox-increased ALD A and GLUT1 levels and attenuated Rox-induced VEC viability, suggesting that Rox-induced HIF-1α contributes to the glycolytic and angiogenic effects of Rox. Rox also promoted tumor growth and angiogenesis and increased the levels of ALD A, GLUT1, and HIF-1α in the tumor tissue of a mouse xenograft model, whereas these effects were abolished using YC-1. Our findings indicated that Rox induces HIF-1α in VECs to promote glycolysis and angiogenesis thus enhancing the tumor growth.

show abstract

Development of Glucose Transporter (GLUT) Inhibitors

Cited by 34 publications

References 46 publications

Changes in Glycolytic Pathway in SARS-COV 2 Infection and Their Importance in Understanding the Severity of COVID-19

Changes in Glycolytic Pathway in SARS-COV 2 Infection and Their Importance in Understanding the Severity of COVID-19

Identification of new GLUT2-selective inhibitors through in silico ligand screening and validation in eukaryotic expression systems

Roxarsone Promotes Glycolysis and Angiogenesis by Inducing Hypoxia-Inducible Factor-1α In Vitro and In Vivo

Contact Info

Product

Resources

About