Εξειδίκευση τύπου :	Περίληψη σε συνέδριο
Τίτλος:	Structure-based design of inhibitors of glycogenolysis, as a promising therapeutic strategy in the treatment of type 2 diabetes
Δημιουργός/Συγγραφέας:	[EL] Οικονομάκος, Νίκος Γ.[EN] Oikonomakos, Nikos G.
Εκδότης:	Springer
Ημερομηνία:	2007
Γλώσσα:	Αγγλικά
ISSN:	0939-4451
DOI:	10.1007/s00726-007-0578-0
Περίληψη:	Efforts towards improving glycaemic control in type 2 diabetes have been directed towards developing inhibitors of glycogen phosphorylase a (GPa) in collaboration with industry (Bayer, Novo Nordisk, Astra Zeneca Pharmaceuticals, and Sanofi-Aventis Pharma). Inhibitors of hepatic GPa have the potential to be effective therapeutic agents for the treatment of type 2 diabetes, as evidenced by studies showing glucose-lowering effects of these compounds. Acyl ureas were recently discovered as novel inhibitors of the enzyme. The X-ray structure of the screening hit 1 (IC50Ό2 mM) revealed that 1 binds at the allosteric site, and induces conformational changes characteristic of a T-state conformation. Two cycles of chemical optimization supported by X-ray structural data of 21 (IC50 of 23 _ 1nM) in complex with human liver GPa (hlGPa) and by a 3D pharmacophore model derived from a training set of 24 compounds led to 42 with improved cellular activity (hlGPa IC50Ό53 _ 1 nM; hepatocyte IC50Ό380nM) and a significant reduction of the glucagon-induced hyperglycemic peak when administered to anaesthetized Wistar rats. Clinical studies to evaluate the use of acyl ureas for the treatment of type 2 diabetes are currently under way. Exposure of hepatocytes to acyl ureas promotes conversion of GPa to inactive GPb because the T-conformation is a better substrate for dephosphorylation by protein phosphatase-1. Since GPa is an allosteric inhibitor of glycogen synthase phosphatase, depletion ofGPa by these compounds leads to sequential activation of glycogen synthase and stimulation of glycogen synthesis. Iminosugars (5, 8, 9), in contrast to acyl ureas inhibitors, promote conversion of GPb to GPa in hepatocytes, with consequent inactivation of glycogen synthase and inhibition of glycogen synthesis. The X-ray structures of 5, 8 and 9 in complex with muscle GPb show that iminosugars bind tightly at the catalytic site in the presence of the substrate phosphate, and induce conformational changes that characterise the R state conformation of the enzyme. Our results suggest that these compounds (IC50Ό0.4–1.2 mM) function as oxocarbenium ion transitionstate analogues: the charged nitrogen N1 is within hydrogen-bonding distance with the carbonyl oxygen of His377 (5) and in ionic contact with the substrate phosphate oxygen (8 and 9). The present evidence from X-ray crystallography that acyl ureas and iminosugars cause the R to T transition and vice versa, respectively, provides the explanation for the metabolic studies in hepatocytes
Όνομα εκδήλωσης:	10th International Congress on Amino Acids and Proteins (ICAAP)
Ημ/νία έναρξης εκδήλωσης :	2007-08-20
Ημ/νία λήξης εκδήλωσης :	2007-08-25
Τόπος εκδήλωσης:	Kallithea, Chalkidiki, Greece
Τίτλος πηγής δημοσίευσης:	Amino Acids
Τόμος/Κεφάλαιο:	33
Τεύχος:	3
Ηλεκτρονική διεύθυνση περιοδικού (link) :	http://www.springerlink.com/content/104405/
ΙΒΦΧΒ: αρχειακή συλλογή:	Ινστιτούτο Οργανικής και Φαρμακευτικής Χημείας (ΙΟΦΧ) (έως 2012)
Εμφανίζεται στις συλλογές:	Ινστιτούτο Χημικής Βιολογίας - Επιστημονικό έργο