Therapeutic potential of breakers of advanced glycation end product-protein crosslinks.
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.
Vasan
Sara
S
Alteon Inc., 170 Williams Drive, Ramsey, NJ 07446, USA. svasan@alteon.com
Foiles
Peter
P
Founds
Hank
H
D000375:Aging / Q000502:physiology; D000818:Animals; D002986:Clinical Trials as Topic; D003432:Cross-Linking Reagents / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000503:physiopathology; D003971:Diastole / Q000187:drug effects / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D004548:Elasticity; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006146:Guanidines / Q000627:therapeutic use; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism; D015394:Molecular Structure; D009206:Myocardium / Q000378:metabolism; D011506:Proteins / Q000737:chemistry*; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry / Q000627:therapeutic use
D003432:Cross-Linking Reagents; D017127:Glycation End Products, Advanced; D006146:Guanidines; D011506:Proteins; D013844:Thiazoles; C406794:alagebrium; C004479:pimagedine