Fox Chase Cancer Center

Benjamin S Szwergold

Francis Kappler

Truman R Brown

Bangying Su

Sundeep Lal

Aqqaluk Peterson

The present invention is based on the discovery of a metabolic pathway in which a specific kinase converts fructose-lysine into fructose-lysine-3-phosphate in an ATP dependent reaction. Fructose-lysine-3-phosphate (FL3P) is then broken down to form free lysine, inorganic phosphate and 3-deoxyglucosone (3DG), the latter being a reactive protein modifying agent. 3DG can be detoxified by reduction to 3-deoxyfructose (3DF), or it can react with endogenous proteins to form advanced glycation end-product modified proteins (AGE-proteins), which are believed to be a cause of diabetic complications. Disclosed is a class of compounds which inhibit the action of FL3P kinase in the above-mentioned pathway. Also disclosed are therapeutic methods of using such inhibitors to reduce formation of AGE-proteins and thereby lessen, reduce and delay diabetic complications, as well as methods for assessing a diabetic's risk of developing complications and for determining the efficacy of the disclosed inhibitor therapy by measuring the ratio of 3DG to 3DF in a biological sample following an oral dose of a fructose-lysine-containing food product.

Compounds and methods for therapeutic intervention in preventing

Concentrations of one or more carbohydrates phosphorylated at a secondary hydroxyl, including fructose-3-phosphate and sorbitol-3-phosphate, in biological tissue or cells of diabetic patients are determined by .sup.31 P NMR Spectroscopy, High Performance Liquid Chromatography (HPLC) or other appropriate analytical techniques. Elevated levels of such phosphorylated carbohydrates, relative to a prescribed standard or threshold level, are associated with an increased risk for developing the degenerative complications of diabetes. A method is provided for determining the relative concentrations of such phosphorylated carbohydrates, whereby the relative risk of a patient for the development of diabetic complications and the efficacy of therapeutic intervention in prevention of such complications may be assessed.

Growing community of inventors

Philadelphia, PA, United States of America

Benjamin S Szwergold