Ligand Screening Systems for Human Glucose Transporters as Tools in Drug Discovery

Abstract

Hexoses are the major source of energy and carbon skeletons for biosynthetic processes in all kingdoms of life. Their cellular uptake is mediated by specialized transporters, including glucose transporters (GLUT, SLC2 gene family). Malfunction or altered expression pattern of GLUTs in humans is associated with several widespread diseases including cancer, diabetes and severe metabolic disorders. Their high relevance in the medical area makes these transporters valuable drug targets and potential biomarkers. Nevertheless, the lack of a suitable high-throughput screening system has impeded the determination of compounds that would enable specific manipulation of GLUTs so far. Availability of structural data on several GLUTs enabled in silico ligand screening, though limited by the fact that only two major conformations of the transporters can be tested. Recently, convenient high-throughput microbial and cell-free screening systems have been developed. These remarkable achievements set the foundation for further and detailed elucidation of the molecular mechanisms of glucose transport and will also lead to great progress in the discovery of GLUT effectors as therapeutic agents. In this mini-review, we focus on recent efforts to identify potential GLUT-targeting drugs, based on a combination of structural biology and different assay systems.

Functional Expression of the Human Glucose Transporters GLUT2 and GLUT3 in Yeast Offers Novel Screening Systems for GLUT-Targeting Drugs

“…The need for a convenient platform to investigate GLUTs has been recognized, and among different systems ( Gould and Lienhard, 1989 ; Zamora-Leon et al, 1996 ; Kraft et al, 2015 ), the yeast cell-based investigation system has many benefits ( Schmidl et al, 2018 ). The yeast Saccharomyces cerevisiae is a widely used GRAS organism and a model organism for diverse research applications.…”

“…The strain is maintained on maltose, a disaccharide taken up by specialized maltose symporters ( Chow et al, 1989 ), and cleaved inside the cell into two glucose molecules. The selective uptake of the respective monosaccharide by a heterologously expressed transporter can, therefore, be examined by simple growth tests or uptake assays with the radiolabeled sugar ( Boles and Oreb, 2018 ; Schmidl et al, 2018 ). Moreover, a radiolabel-free assay to determine transport kinetics in the hxt 0 yeast system has been recently developed ( Schmidl et al, 2021 ).…”

DockNmine, a Web Portal to Assemble and Analyse Virtual and Experimental Interaction Data

“…To move towards precision medicine, dockNmine can act as a central gathering portal to add much more experimental and docking information. In the case of the GLUT members, this would required adding docking and experimental data for the 14 members of the SLC2 family, from the recently published study in Reference [41,42].…”

Fluorescent conjugates of D-glucosamine with 3-thiazolylcoumarins: synthesis, characterization and potential use as cell imaging agents

“…Fluorescent conjugates of glucose and its analogs have been used e.g. for the studies of glucose transport [11][12][13], construction of screening systems for drug discovery [14][15][16], imaging of tumors [17,18] and pancreatic beta and alpha cells [19].…”

“…Glucose and its derivatives get into the cell mainly through GLUTs (Glucose Transporters), membrane proteins facilitating the glucose transport across the cell membrane [30,31]. Sugar-drug conjugates are extensively used in cell imaging and drug delivery systems based on monosaccharide transport proteins [10,15,16,31]. Main requirements for the efficient uptake of the conjugates are as small as possible size of the aglycone and the absence of permanently charged groups [26,32].…”