Vasan Sara, Foiles Peter, Founds Hank
Alteon Inc., 170 Williams Drive, Ramsey, NJ 07446, USA.
Arch Biochem Biophys. 2003 Nov 1;419(1):89-96. 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.
长寿结构蛋白胶原蛋白和弹性蛋白在衰老过程以及糖尿病患者体内会持续发生非酶促交联。这种异常的蛋白质交联是由葡萄糖对蛋白质进行非酶糖基化产生的晚期糖基化终产物（AGEs）介导的。结构蛋白的AGE衍生蛋白交联会导致长期糖尿病的并发症，如肾病、视网膜病变和神经病变。AGE交联还与年龄相关的心血管疾病有关。针对这些AGE衍生并发症的潜在治疗策略包括预防AGE的形成以及破坏现有的AGE交联。AGE抑制剂氨基胍在动物模型和3期临床试验中已对其治疗潜力进行了广泛研究。本综述介绍了使用ALT-711进行的临床前和临床研究，ALT-711是一种高效的AGE交联破坏剂，能够逆转已形成的AGE交联。在实验动物中，口服ALT-711可迅速改善硬化心肌的弹性。局部应用ALT-711可有效改善老年大鼠的皮肤水合作用。本文还讨论了交联破坏剂对与衰老和糖尿病相关的心血管并发症及皮肤改变的治疗潜力。
