The Design of a GLP‐1/PYY Dual Acting Agonist

• Published in: Angewandte Chemie International Edition Vol. 60; no. 15; pp. 8268 - 8275
• Main Authors: Østergaard, Søren, Paulsson, Johan F., Kjærgaard Gerstenberg, Marina, Wulff, Birgitte S.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 06.04.2021
• Edition: International ed. in English
• Subjects: Agonists; drug design; dual agonists; Food; Food intake; GLP-1; Homology; Hormones; obesity; Receptors; structure-activity relationships; GLP-1; structure-activity relationships; drug design; obesity; dual agonists
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202016464

The two gut hormones GLP‐1 and PYY3–36, which are both secreted from the L‐cells upon food stimuli, have a stronger inhibitory effect on food intake when they are combined, compared to their individual effects as single agonists. Although they are not homologous and share no sequence similarity, we show that a GLP‐1 analogue can be designed to exhibit potent activity on both the Y2 and GLP‐1 receptors. Dual acting hybrid analogues were realized by designing truncated and potent Y2 receptor PYY analogues, followed by integrating the critical residues into GLP‐1. In this study, we show that one of these dual acting agonists acutely reduces food intake significantly more than the respective mono‐agonist counterparts. A GLP‐1/PYY hybrid analogue of the two non‐homologous peptides, GLP‐1 and PYY, activating both GLP‐1 and Y2 receptors that belong to different receptor families, was designed and shown to have increased in vivo efficacy compared to the mono‐agonist analogue versions in an acute food intake study in mice.