Therapeutic potential of breakers of advanced glycation end product–protein crosslinks

• Published in: Archives of Biochemistry and Biophysics 2003-11, Vol.419 (1), p.89-96
• Main Authors: Vasan, Sara, Foiles, Peter, Founds, Hank
• Format: Article
• Language: English
• Subjects: Advanced glycation end products; Aging - physiology; ALT-711; Animals; Arterial stiffness; Clinical Trials as Topic; Cross-Linking Reagents - metabolism; Crosslink breakers; Diabetes Mellitus - drug therapy; Diabetes Mellitus - physiopathology; Diastole - drug effects; Diastole - physiology; Diastolic dysfunction; Drug Evaluation, Preclinical; Elasticity; Glycation End Products, Advanced - antagonists & inhibitors; Glycation End Products, Advanced - metabolism; Guanidines - therapeutic use; Humans; Hypertrophy, Left Ventricular - metabolism; Left ventricular hypertrophy; Molecular Structure; Myocardium - metabolism; Proteins - chemistry; Skin - drug effects; Skin - metabolism; Thiazoles - chemistry; Thiazoles - therapeutic use
• ISSN: 0003-9861; 1096-0384
• DOI: 10.1016/j.abb.2003.08.016

Long-lived structural proteins, collagen and elastin, undergo continual non-enzymatic crosslinking during aging and in diabetic individuals. This abnormal protein crosslinking is mediated by advanced glycation end products (AGEs) generated by non-enzymatic glycosylation of proteins by glucose. The AGE-derived protein crosslinking of structural proteins contributes to the complications of long-term diabetes such as nephropathy, retinopathy, and neuropathy. AGE-crosslinks have also been implicated in age-related cardiovascular diseases. Potential treatment strategies for these AGE-derived complications include prevention of AGE-formation and breaking of the existing AGE-crosslinks. The therapeutic potential of the AGE-inhibitor, pimagedine (aminoguanidine), has been extensively investigated in animal models and in Phase 3 clinical trials. This review presents the pre-clinical and clinical studies using ALT-711, a highly potent AGE-crosslink breaker that has the ability to reverse already-formed AGE-crosslinks. Oral administration of ALT-711 has resulted in a rapid improvement in the elasticity of stiffened myocardium in experimental animals. Topical administration of ALT-711 was effective in improving the skin hydration of aged rats. The therapeutic potential of crosslink breakers for cardiovascular complications and dermatological alterations associated with aging and diabetes is discussed.