Development of a Long-Acting and Stapled Dual Amylin and Calcitonin Receptor Agonist as Monotherapy and Combination with GLP-1R Agonists for the Treatment of Obesity.

Dual amylin and calcitonin receptor agonists (DACRAs) offer a promising strategy for treating obesity and related metabolic disorders but are limited by aggregation and the short half-lives of native peptides. Here, we report the design of a long-acting and stapled DACRA via a streamlined on-resin Ugi macrocyclization strategy based on a salmon calcitonin template. The lead candidate UDA-6 exhibited potent and balanced activation of AMYR and CTR, with enhanced helical stability and favorable pharmacokinetics properties supporting once-weekly dosing. In diet-induced obese rats, UDA-6 elicited substantial weight loss and improved metabolic and hepatic parameters. Combination therapy of UDA-6 with semaglutide or tirzepatide yielded synergistic efficacies, achieving up to 41% vehicle-adjusted body-weight reduction and near-normalized liver lipid profiles. These findings establish UDA-6 as a potent and durable DACRA and highlight Ugi macrocyclization as a versatile platform for the long-acting peptide drug design.