Development of the novel amylin and calcitonin receptor activators by peptide mutagenesis.

The amylin peptide hormone receptor is the complex of the calcitonin peptide hormone receptor and an accessory protein. The calcitonin receptor activation controls calcium homeostasis, while it also functions as the main component of the amylin receptor. Amylin receptor activation in brains controls blood glucose and appetite. Currently, non-selective amylin and calcitonin receptor activators have been tested for body weight reduction to treat obesity. Here, multiple peptide activators for human amylin and calcitonin receptors were developed by introducing comprehensive mutagenesis to rat amylin peptide. The rat amylin peptide C-terminal fragment that interacts with amylin receptor extracellular domain was used to screen for affinity-enhancing mutations. Up to twelve mutational combinations were found to significantly increase peptide affinity both for amylin and calcitonin receptor extracellular domains by over 100-fold. Using these affinity-enhancing mutations, three representative rat amylin analogs with thirty-seven amino acids were made to test the potency increase for amylin and calcitonin receptor activation. All three mutated rat amylin analogs showed significant potency increases by 5- to 10-fold compared to endogenous rat amylin. These mutated peptide activators also showed higher potency for human amylin and calcitonin receptor activation than a clinically available amylin receptor activator pramlintide. These amylin and calcitonin receptor activators developed in this study may be useful as the valuable pharmacological tools that activate amylin receptors in cell-based systems.

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