Variant fatty acid-like molecules Conjugation, novel approaches for extending the stability of therapeutic peptides.
Variant fatty acid-like molecules Conjugation, novel approaches for extending the stability of therapeutic peptides.
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变体脂肪酸类分子缀合，延长治疗性肽稳定性的新方法
DOI：
10.1038/srep18039
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发表时间：
2015-12-11
影响因子：
4.6
通讯作者：
Gong M
中科院分区：
文献类型：
--
作者：
Li Y;Wang Y;Wei Q;Zheng X;Tang L;Kong D;Gong M
胰高血糖素样肽-1（GLP-1）的多种生理特性使其成为治疗2型糖尿病的有希望的候选药物。然而，由于二肽基肽酶-IV（DPP-IV）的快速降解和肾清除，GLP-1的体内半衰期较短。GLP-1的稳定性较差，严重限制了其临床应用;然而，许多研究都集中在延长其稳定性上。由于人血清白蛋白对脂肪酸的高结合亲和力，脂肪酸缀合是用于延长治疗性肽的稳定性的传统方法。然而，缀合物需要复杂的合成方法，通常涉及Lys并且偶尔涉及接头。在目前的研究中，我们将GLP-1分子与脂肪酸衍生物结合，以简化合成步骤。人血清白蛋白结合试验表明，保留的羧基的脂肪酸有助于保持紧密的亲和力，HSA。脂肪酸样分子的缀合改善了GLP-1的稳定性并增加了GLP-1与HSA的结合亲和力。使用脂肪酸样分子作为缀合组分允许变体缀合位置和游离羧基用于其他潜在用途。这可能是开发治疗性肽的一种新型长效策略。
The multiple physiological properties of glucagon-like peptide-1 (GLP-1) make it a promising drug candidate for the treatment of type 2 diabetes. However, the in vivo half-life of GLP-1 is short due to rapid degradation by dipeptidyl peptidase-IV (DPP-IV) and renal clearance. The poor stability of GLP-1 has significantly limited its clinical utility; however, many studies are focused on extending its stability. Fatty acid conjugation is a traditional approach for extending the stability of therapeutic peptides because of the high binding affinity of human serum albumin for fatty acids. However, the conjugate requires a complex synthetic approach, usually involving Lys and occasionally involving a linker. In the current study, we conjugated the GLP-1 molecule with fatty acid derivatives to simplify the synthesis steps. Human serum albumin binding assays indicated that the retained carboxyl groups of the fatty acids helped maintain a tight affinity to HSA. The conjugation of fatty acid-like molecules improved the stability and increased the binding affinity of GLP-1 to HSA. The use of fatty acid-like molecules as conjugating components allowed variant conjugation positions and freed carboxyl groups for other potential uses. This may be a novel, long-acting strategy for the development of therapeutic peptides.