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.

This study demonstrates the efficacy of single α-amino acids substitution with ureido residues to design long lasting peptides.

Cyclizations of stilbenecarboxylic acids to the corresponding isocoumarin derivatives using diselenide or disulfide reagents have been developed. By employing bis(triflouroacetoxy)iodobenzene as oxidant for the 6‐endo‐trig cyclizations a variety of dihydroisocoumarins have been prepared in good yields. This method is capable of forming isocoumarins and dihydroisocoumarin derivatives by a cyclization–elimination route.

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