DPP-IV-resistant, long-acting oxyntomodulin derivatives
DPP-IV-resistant, long-acting oxyntomodulin derivatives
复制标题
DOI：
10.1002/psc.1328
复制
发表时间：
2011-04-01
影响因子：
2.1
通讯作者：
Pessi, Antonello
中科院分区：
文献类型：
--
作者：
Santoprete, Alessia;Capito, Elena;Pessi, Antonello
肥胖是2型糖尿病的主要危险因素之一，人们正在积极开发能够同时实现血糖控制和减肥的药物。基于肠道激素胰高血糖素样肽 1 (GLP-1) 的肽模拟物的疗法迅速受到青睐，因为它们能够以严格的葡萄糖依赖性方式增加胰岛素分泌，几乎没有或没有低血糖的风险，而且还具有引起适度但持久的体重减轻的额外好处。泌酸调节素 (OXM) 是一种胰高血糖素 (GCG) 家族的 37 个氨基酸肽激素，对 GLP-1 (GLP1R) 和 GCG (GCGR) 受体具有双重激动活性，已被证明可以减少人类的食物摄入量和体重，并且与 GLP-1 模拟物相比，治疗相关的恶心发生率较低。至于其他肽激素，其临床应用受到短循环半衰期的限制，其主要成分是被二肽基肽酶IV（DPP-IV）裂解。本文所述的 OXM SAR 研究导致鉴定出抗 DPP-IV 降解的分子，与天然激素相比，其效力增强。用胆固醇部分衍生的类似物显示出体内作用持续时间增加。此外，我们还发现了一个单一取代，可以将 OXM 药理学特征从双重 GLP1R/GCGR 激动剂改变为选择性 GLP1R 激动剂。后一个发现促成了研究，在另一项研究中详细描述了（Pocai A、Carrington PE、Adams JR、Wright M、Eiermann G、Zhu L、Du X、Petrov A、Lassman ME、Jiang G、Liu F、Miller C、Tota LM、Zhou G、Zhang X、Sountis MM、Santoprete A、Capito E、Chicchi GG、Thornberry N、Bianchi E、Pessi A、Marsh DJ， SinhaRoy R. 胰高血糖素样肽 1/胰高血糖素受体双重激动剂可逆转小鼠肥胖，2009 年；58：2258-2266），这凸显了 GLP1R/GCGR 双重激动剂作为一种潜在的优于目前临床使用的纯 GLP1R 激动剂的治疗方法的潜力。版权所有 (C) 2011 欧洲肽协会和 John Wiley & Sons, Ltd.
Obesity is one of the major risk factors for type 2 diabetes, and the development of agents, that can simultaneously achieve glucose control and weight loss, is being actively pursued. Therapies based on peptide mimetics of the gut hormone glucagon-like peptide 1 (GLP-1) are rapidly gaining favor, due to their ability to increase insulin secretion in a strictly glucose-dependent manner, with little or no risk of hypoglycemia, and to their additional benefit of causing a modest, but durable weight loss. Oxyntomodulin (OXM), a 37-amino acid peptide hormone of the glucagon (GCG) family with dual agonistic activity on both the GLP-1 (GLP1R) and the GCG (GCGR) receptors, has been shown to reduce food intake and body weight in humans, with a lower incidence of treatment-associated nausea than GLP-1 mimetics. As for other peptide hormones, its clinical application is limited by the short circulatory half-life, a major component of which is cleavage by the enzyme dipeptidyl peptidase IV (DPP-IV). SAR studies on OXM, described herein, led to the identification of molecules resistant to DPP-IV degradation, with increased potency as compared to the natural hormone. Analogs derivatized with a cholesterol moiety display increased duration of action in vivo. Moreover, we identified a single substitution which can change the OXM pharmacological profile from a dual GLP1R/GCGR agonist to a selective GLP1R agonist. The latter finding enabled studies, described in detail in a separate study (Pocai A, Carrington PE, Adams JR, Wright M, Eiermann G, Zhu L, Du X, Petrov A, Lassman ME, Jiang G, Liu F, Miller C, Tota LM, Zhou G, Zhang X, Sountis MM, Santoprete A, Capito E, Chicchi GG, Thornberry N, Bianchi E, Pessi A, Marsh DJ, SinhaRoy R. Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in mice. Diabetes 2009; 58: 2258-2266), which highlight the potential of GLP1R/GCGR dual agonists as a potentially superior class of therapeutics over the pure GLP1R agonists currently in clinical use. Copyright (C) 2011 European Peptide Society and John Wiley & Sons, Ltd.