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

The two gut hormones GLP-1 and PYY_3-36 , 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.