UREKA-ImmuPharma Group, 2 rue Robert Escarpit, 33607, Pessac, France.
Univ. Bordeaux, CNRS, CBMN, UMR 5248, Institut Européen de Chimie et Biologie, 2 rue Robert Escarpit, 33607, Pessac, France.
Nat Commun. 2019 Feb 25;10(1):924. doi: 10.1038/s41467-019-08793-y.
Peptides have gained so much attention in the last decade that they are now part of the main strategies, with small molecules and biologics, for developing new medicines. Despite substantial progress, the successful development of peptides as drugs still requires a number of limitations to be addressed, including short in vivo half-lives and poor membrane permeability. Here, we describe the use of oligourea foldamers as tool to improve the pharmaceutical properties of GLP-1, a 31 amino acid peptide hormone involved in metabolism and glycemic control. Our strategy consists in replacing four consecutive amino acids of GLP-1 by three consecutive ureido residues by capitalizing on the structural resemblance of oligourea and α-peptide helices. The efficacy of the approach is demonstrated with three GLP-1-oligourea hybrids showing prolonged activity in vivo. Our findings should enable the use of oligoureas in other peptides to improve their pharmaceutical properties and may provide new therapeutic applications.
在过去的十年中，肽引起了广泛关注，它们现在是小分子和生物制剂开发新药的主要策略之一。尽管取得了重大进展，但肽作为药物的成功开发仍需要解决许多限制因素，包括体内半衰期短和膜通透性差。在这里，我们描述了使用寡脲折叠物来改善 GLP-1 的药物特性的方法，GLP-1 是一种 31 个氨基酸的肽激素，参与代谢和血糖控制。我们的策略包括通过利用寡脲和 α-肽螺旋的结构相似性，用三个连续的脲基残基取代 GLP-1 的四个连续氨基酸。通过三种 GLP-1-寡脲杂合体在体内延长活性，证明了该方法的有效性。我们的发现应该能够在其他肽中使用寡脲来改善它们的药物特性，并可能提供新的治疗应用。
