Istituto di Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy.
J Pept Sci. 2011 Apr;17(4):270-80. doi: 10.1002/psc.1328. Epub 2011 Feb 3.
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, Capitò 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.
肥胖是 2 型糖尿病的主要危险因素之一，因此正在积极开发能够同时实现血糖控制和体重减轻的药物。基于肠激素胰高血糖素样肽 1（GLP-1）类似物的疗法因其能够以严格依赖葡萄糖的方式增加胰岛素分泌、低血糖风险小或无、以及引起适度但持久的体重减轻的额外益处而迅速受到青睐。胆囊收缩素（GCG）家族的 37 个氨基酸肽激素奥曲肽（OXM）对 GLP-1（GLP1R）和 GCG（GCGR）受体均具有双重激动活性，已被证明可减少人类的食物摄入和体重，与 GLP-1 类似物相比，治疗相关恶心的发生率较低。与其他肽激素一样，其临床应用受到循环半衰期短的限制，其中主要成分是被二肽基肽酶 IV（DPP-IV）切割。本文所述的 OXM 的 SAR 研究导致了鉴定出对 DPP-IV 降解具有抗性的分子，与天然激素相比，其效力增加。用胆固醇部分衍生的类似物在体内显示出更长的作用持续时间。此外，我们确定了一个单一取代可以将 OXM 的药理学特性从双重 GLP1R/GCGR 激动剂改变为选择性 GLP1R 激动剂。后一项发现使我们能够进行详细描述的研究（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、Capitò 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肥胖小鼠的病情。糖尿病 2009; 58: 2258-2266），这些研究强调了 GLP1R/GCGR 双重激动剂作为一种潜在的治疗方法，优于目前临床使用的纯 GLP1R 激动剂。
