Investigation of Structure-Activity Relationships of Oxyntomodulin (Oxm) Using Oxm Analogs
Investigation of Structure-Activity Relationships of Oxyntomodulin (Oxm) Using Oxm Analogs
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DOI：
10.1210/en.2008-0828
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发表时间：
2009-04-01
期刊：
影响因子：
4.8
通讯作者：
Bloom, Stephen R.
中科院分区：
文献类型：
--
作者：
Druce, Maralyn R.;Minnion, James S.;Bloom, Stephen R.
胃泌酸调节素（Oxm）是一种抑制啮齿动物和人类食物摄入和体重的肠肽。这些研究使用肽类似物来研究Oxm的结构和功能方面，以及Oxm序列的部分对降解的敏感性。Oxm的类似物的合成和研究使用受体结合和体外降解研究。在啮齿类动物体内测量它们对食物摄入和条件性味觉回避的影响。在体外和体内证明了由酶二肽基肽酶IV（DPPIV）引起的Oxm分解。DPPIV抑制剂可降低体外降解，提高体内生物活性。对Oxm的N末端的修饰调节与胰高血糖素样肽（GLP）-1受体的结合和DPPIV的降解。对Oxm中段的修饰调节了与GLP-1受体的结合和中性内肽酶的降解。这些修饰也改变了体内生物活性。Oxm的C-末端八肽被证明有助于Oxm在体外和体内的性质，但单独的肽的效果是不够的。Oxm C末端的延长和酰化改变了GLP-1受体结合和体内作用持续时间，这可能是由于肽清除率的变化。开发了具有增强的药物特性的Oxm类似物，其在对食物摄入的影响方面具有更大的效力和寿命。这些研究表明，Oxm是一个潜在的抗肥胖药物设计的目标。（内分泌学150：1712 - 1721，2009）
Oxyntomodulin (Oxm) is an intestinal peptide that inhibits food intake and body weight in rodents and humans. These studies used peptide analogs to study aspects of structure and function of Oxm, and the sensitivity of parts of the Oxm sequence to degradation. Analogs of Oxm were synthesized and studied using receptor binding and degradation studies in vitro. Their effects on food intake and conditioned taste avoidance were measured in vivo in rodents. Oxm breakdown by the enzyme dipeptidyl peptidase IV (DPPIV) was demonstrated in vitro and in vivo. In vitro degradation was reduced and in vivo bioactivity increased by inhibitors of DPPIV. Modifications to the N terminus of Oxm modulated binding to the glucagon-like peptide (GLP)-1 receptor and degradation by DPPIV. Modifications to the midsection of Oxm modulated binding to the GLP-1 receptor and degradation by neutral endopeptidase. These modifications also altered bioactivity in vivo. The C-terminal octapeptide of Oxm was shown to contribute to the properties of Oxm in vitro and in vivo but was not alone sufficient for the effects of the peptide. Elongation and acylation of the C terminus of Oxm altered GLP-1 receptor binding and duration of action in vivo, which may be due to changes in peptide clearance. An Oxm analog was developed with enhanced pharmaceutical characteristics, with greater potency and longevity with respect to effects on food intake. These studies suggest that Oxm is a potential target for antiobesity drug design. (Endocrinology 150: 1712-1721, 2009)