Ichikawa Megumi, Hirayama Tetsuya, Fukushima Masanobu, Kitazawa Ikue, Kojima Kazuhiro, Sakai Tokiko, Takatsu Yoshihiro, Ohtaki Tetsuya
Central Research Laboratories, Seikagaku Corporation, Tateno 3-1253, Higashiyamato-shi, Tokyo 207-0021, Japan.
ACS Omega. 2018 May 31;3(5):5346-5354. doi: 10.1021/acsomega.8b00467. Epub 2018 May 18.
Glucagon-like peptide-1 (GLP-1) is an incretin peptide that plays a crucial role in lowering blood glucose levels and holds promise for treating type II diabetes. In this study, we synthesized GLP-1 derivatives that were conjugated with glycosaminoglycans (GAGs), i.e., chondroitin (CH) or heparosan (HPN), to address the major limitation in their clinical use of GLP-1, which is its short half-life in the body. After exploring a variety of CHs with different molecular sizes and heterobifunctional linkers having different alkyl chains, we obtained CH-conjugated GLP-1 derivatives that stayed in blood circulation much longer ( > 25 h) than unconjugated GLP-1 and showed blood glucose-lowering efficacy up to 120 h after subcutaneous injection in mice. By using the same optimized linker design, we eventually obtained a HPN-conjugated GLP-1 derivative with efficacy lasting 144 h. These results demonstrate that conjugation with GAG is a promising strategy for improving the duration of peptide drugs.
胰高血糖素样肽-1（GLP-1）是一种肠促胰岛素肽，在降低血糖水平方面发挥着关键作用，有望用于治疗II型糖尿病。在本研究中，我们合成了与糖胺聚糖（GAGs），即软骨素（CH）或肝素聚糖（HPN）偶联的GLP-1衍生物，以解决GLP-1临床应用中的主要局限性，即其在体内的半衰期较短。在探索了各种不同分子大小的CHs和具有不同烷基链的异双功能连接体后，我们获得了与CH偶联的GLP-1衍生物，其在血液循环中的停留时间比未偶联的GLP-1长得多（>25小时），并且在小鼠皮下注射后120小时内显示出降血糖功效。通过使用相同的优化连接体设计，我们最终获得了一种功效持续144小时的与HPN偶联的GLP-1衍生物。这些结果表明，与GAG偶联是延长肽类药物作用持续时间的一种有前景的策略。
