Institute of Organic and Pharmaceutical Chemistry
The National Hellenic Research Foundation
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Control of glycogen metabolism
Diabetes is a major cause of blindness and renal disease, and is known to significantly increase the risk of cardiovascular disease, leading to heart attack, stroke and amputation of the lower extremity(ies). Almost 90% of all diabetics are type 2 (T2D) and cannot be treated with exogenous insulin. T2D (non insulin-dependent diabetes mellitus) afflicts 23 million people in Europe and will soon be one of the world’s commonest diseases. The global incidence of T2D is projected to afflict more than 300 million people worldwide by the year 2005, and many of those affected will be young adults. The costs of T2D medication exceed 4% of the annual health care budget in EU countries. Current preventative and therapeutic strategies are inadequate, and there is a need for the research community (both academic and industrial) to develop novel healthcare interventions to address this substantial biomedical challenge. T2D is characterized by excessive glucose production from the liver.
A molecular approach, aimed at reducing excessive glucose production from the liver involves the identification and optimization of novel, potent and selective inhibitors of glycogen phosphorylase (EC 2.4.1.1; GP), a rate controlling enzyme of the glycogenolytic pathway. In fact, inhibitors of GP have been proposed as a therapeutic strategy for improving glycaemic control in T2D mellitus and various studies have shown the efficacy of such compounds at lowering blood glucose or inhibiting liver glycogenolysis in vitro or in vivo. In our group the design of GP inhibitors is the focus of much effort to find new compounds to treat T2D.
Inhibitor design for GP targets the AMP activatory and the glucose-6-P inhibitory allosteric sites, the catalytic site that binds glycogen and glucose-1-P, the inhibitor site located 12 Å from the catalytic site and which binds caffeine and heterocyclic compounds such as flavopiridol, and a novel allosteric inhibitor site, shown to bind a number of indole-2-carboxamide inhibitors. In this project we wish to extend our knowledge on molecular recognition of small molecules by the catalytic site of GP and to develop new potent inhibitors by using as scaffolds the inhibitor N-acetyl-b-D-glucopyranosylamine, glucopyranosyl ureas, analogues of flavopiridol and indirubin, acyl ureas and inhibitors derived from virtual ligand screening. The project adopts a multidisciplinary approach to go from a protein crystal structure to the development of high affinity inhibitors.
Another target is phosphorylase kinase (PhK), the enzyme that integrates signals from hormonal messengers and neuronal stimuli to produce rapid activation of glycogen phosphorylase and subsequent degradation of glycogen stores either to provide energy to sustain muscle contraction or in the liver, to provide other tissues such as the brain with glucose. It is one of the most complex kinases comprising (αbγd)4 assembly of subunits with a total molecular weight of 1.3 x 106. Our task is to screen a new class of inhibitors with both the PhKγtrunc and the holoenzyme kinetically and crystallographically.
Research Interests:
Control of glycogen metabolism
Phosphoenolpyruvate carboxykinase
Carbohydrate
recognition
Human TAFs9 proteins
Xylanases and feruloyl esterases
