Among GLUTs, GLUT1 is arguably the most studied and several inhibitors for its activity have been described, including forskolin and cytochalasin B12. Consistent with the significant sequence conservation within the GLUT family, known GLUT inhibitors often affect more than one family member. For instance, forskolin and cytochalasin B inhibit other glucose transporters, such as human GLUT2 and GLUT413 and even the bacterial glucose/H+ symporter GlcPSe14, though not GLUT515. Given its limited tissue expression and particular pattern of overexpression in diseases, GLUT5 could be an important target for therapeutic intervention, however no inhibitor of its activity has been reported. In general, finding ligands specific for a single GLUT protein would be a significant step forward in the development of therapeutic inhibitors of GLUTs. In particular, as GLUT1 is ubiquitously expressed in adult humans, viable drugs against GLUT5 should minimally impact GLUT1.
Indeed, a recent study found two natural products that inhibit GLUT5; one of which, rubusoside, a natural sweetener from the Chinese sweet tea plant (Rubus suavissimus), inhibited both GLUT1 and GLUT5, the first example of a common inhibitor for these two GLUTs. The other molecule, astragalin-6-glucoside, a flavonoid compound from the American pokeweed (Phytolacca americana) did not affect GLUT1. These inhibitors, though not potent (IC50 values ~ 5 mM) allowed for the identification of active site differences between GLUT1 and GLUT5 responsible for ligand specificity17.
Viable drugs targeting the fructose transport of GLUT5 should not interfere with transport mediated by other GLUT proteins. For instance, disrupting glucose transport by the insulin-dependent GLUT4 can lead to diabetes19. GLUT1, another transporter of glucose, is expressed in most tissues, so its inhibition can cause serious side effects at the organism level. Ideally, GLUT5 specific inhibitors should only affect GLUT5 mediated fructose transport, without altering aspects of metabolism unrelated to fructose consumption.