Discovery of TL10:A Soluble and Long-Acting MC4RAgonist with Tunable Lipidation for Sustained Pharmacological Activity

Abstract The development of long-acting MC4R peptide agonists remains challenging due to rapid clearance and structural sensitivity, where conventional permanent lipidation strategies often impair receptor engagement. Here, we report the discovery and characterization of TL10, a soluble, long-acting MC4R agonist achieved via a tunable lipidation strategy that transiently masks the peptide to extend circulation while preserving activity. TL10 exhibited controlled release kinetics and a markedly prolonged plasma half-life (t1/2 ≈ 33.4 h), representing a 34-fold increase compared to setmelanotide. In diet-induced obese mice, Q3D administration of TL10 elicited sustained weight loss and appetite suppression, matching or exceeding daily setmelanotide under the tested conditions. High aqueous solubility (180 mg/mL) facilitated concentrated formulations, and a 28 day repeat-dose study indicated a favorable safety profile. Collectively, these results demonstrate that TL10 is a promising long-acting candidate with sustained pharmacological activity, providing a practical framework for the development of modification-sensitive peptides.