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A series of G s protein peptidomimetics were designed and synthesised based on the published X-ray crystal structure of the active state β 2 -adrenergic receptor (β 2 AR) in complex with the G s protein (PDB 3SN6). We hypothesised that such peptidomimetics may function as allosteric modulators that target the intracellular G s protein binding site of the β 2 AR. Peptidomimetics were designed to mimic the 15 residue C-terminal α-helix of the G s protein and were pre-organised in a helical conformation by ( i , i + 4)-stapling using copper catalysed azide alkyne cycloaddition. Linear and stapled peptidomimetics were analysed by circular dichroism (CD) and characterised in a membrane-based cAMP accumulation assay and in a bimane fluorescence assay on purified β 2 AR. Several peptidomimetics inhibited agonist isoproterenol (ISO) induced cAMP formation by lowering the ISO maximal efficacy up to 61%. Moreover, some peptidomimetics were found to significantly decrease the potency of ISO up to 39-fold. In the bimane fluorescence assay none of the tested peptidomimetics could stabilise an active-like conformation of β 2 AR. Overall, the obtained pharmacological data suggest that some of the peptidomimetics may be able to compete with the native G s protein for the intracellular binding site to block ISO-induced cAMP formation, but are unable to stabilise an active-like receptor conformation.

Gsprotein peptidomimetics as allosteric modulators of the β2-adrenergic receptor

G_sprotein peptidomimetics as allosteric modulators of the β₂-adrenergic receptor