With cardiovascular diseases being the lead cause of mortality in obese patients there is a significant unmet medical need to develop novel drugs targeting not only obesity, but also obesity associated cardiovascular diseases. We hypothesize that combining the anti-obesity and glucoregulatory properties of amylin with the cardioprotective effects of adrenomedullin could be an effective treatment strategy to address both. We report the chemical feasibility and receptor potencies of unimolecular peptide agonists with dual activity at the amylin and adrenomedullin receptors.
Using solid-phase peptide synthesis, an array of hybrid peptides was rationally designed by substituting amino acids essential for amylin activity into the native adrenomedullin sequence. Also, the peptide backbones were subjected to N-terminal lipidation with a C20 di-acid as a half-life extension strategy. The functional activities of the dual agonists were measured using a cAMP accumulation assays in U2OS cells overexpressing the human amylin receptor subtype 3 (hAMY3-R) and in CHO-K1 cells overexpressing the human adrenomedullin receptor subtype 1 (hAM1-R).
All analogues were full agonists on both receptors. Potencies on the hAMY3-R were comparable to human amylin while potencies on the hAM1-R came in a range from equipotent to 100-fold less potent as compared to human adrenomedullin. One of the most potent analogues had EC50 values of 0.06 ± 0.01 and 11.40 ± 1.08 nM on hAMY3-R and hAM1-R, respectively, compared with amylin (EC50= 0.01 ± 0.01 nM on hAMY3-R) and adrenomedullin (EC50= 1.73 ± 0.24 nM on hAM1-R).
We demonstrated chemical feasibility of novel hybrid amylin-adrenomedullin peptide agonists with dual activity at the hAMY3-R and hAM1-R for the potential treatment of obesity patients with high cardiovascular risk. Future directions include in vivo studies to access the efficacy and potency of the novel dual agonists.