The Retro-2 molecule protects cells against Shiga toxins by specifically blocking retrograde transport from early endosomes to the trans-Golgi network. A SAR study has been carried out to identify more potent compounds. Cyclization and modifications of Retro-2 led to a compound with roughly 100-fold improvement of the EC50 against Shiga toxin cytotoxicity measured in a cell protein synthesis assay. We also demonstrated that only one enantiomer of the dihydroquinazolinone reported herein is bioactive.

Stolarczyk E, Guissard C, Michau A, Even PC, Grosfeld A, Serradas P, Lorsignol A, Pénicaud L, Brot-Laroche E, Leturque A, Le Gall M. Detection of extracellular glucose by GLUT2 contributes to hypothalamic control of food intake. Am J Physiol Endocrinol Metab 298: E1078 -E1087, 2010. First published February 23, 2010 doi:10.1152/ajpendo.00737.2009.-The sugar transporter GLUT2, present in several tissues of the gut-brain axis, has been reported to be involved in the control of food intake. GLUT2 is a sugar transporter sustaining energy production in the cell, but it can also function as a receptor for extracellular glucose. A glucose-signaling pathway is indeed triggered, independently of glucose metabolism, through its large cytoplasmic loop domain. However, the contribution of the receptor function over the transporter function of GLUT2 in the control of food intake remains to be determined. Thus, we generated transgenic mice that express a GLUT2-loop domain, blocking the detection of glucose but leaving GLUT2-dependent glucose transport unaffected. Inhibiting GLUT2-mediated glucose detection augmented daily food intake by a mechanism that increased the meal size but not the number of meals. Peripheral hormones (ghrelin, insulin, leptin) were unaffected, leading to a focus on central aspects of feeding behavior. We found defects in c-Fos activation by glucose in the arcuate nucleus and changes in the amounts of TRH and orexin neuropeptide mRNA, which are relevant to poorly controlled meal size. Our data provide evidence that glucose detection by GLUT2 contributes to the control of food intake by the hypothalamus. The sugar transporter receptor, i.e., "transceptor" GLUT2, may constitute a drug target to treat eating disorders and associated metabolic diseases, particularly by modulating its receptor function without affecting vital sugar provision by its transporter function. glucose transporter 2; sugar sensing; SLC2A2 THE HYPOTHALAMUS RECEIVES AND INTEGRATES central and peripheral signals that regulate feeding behavior to adapt nutrient ingestion to energy expenditure. Peripheral hormones secreted by the digestive tract (ghrelin, glucagon-like peptide-1, peptide YY, and cholecystokinin), the pancreas (insulin), and the adipose tissue (leptin, adiponectin) are translated by the hypothalamus into the production of orexigenic [neuropeptide Y (NPY), Agouti-related protein (AgRP), orexin, melanin-concentrating hormone (MCH)] or anorexigenic [proopiomelanocortin (POMC), cocaine-and amphetamine-regulated transcript (CART), thyrotropin-releasing hormone (TRH), corticotropin-releasing hormone (CRH)] peptides (reviewed in Refs. 3 and 10). The resulting arcuate and paraventricular hypothalamic neuronal activity leads to appropriate meal number and size (3). In addition to the integration of hormonal signals, the brain can also directly sense nutrients, and glucose plays a particular role as main energy source for brain cells. The glucostatic theory for the regulation of food intake (37) has postulated that energy needs a...