Eleven novel analogs of setmelanotide are reported in which the labile disulfide bond is replaced with robust carbon-based linker groups. Linkers of variable size and rigidity are well tolerated, with heteroatom- and π-based linkers displaying optimal potency. These findings present opportunities to develop variants of setmelanotide that address monogenic obesity, metabolic diseases, and weight loss.
The melanocortin 4 receptor (MC4R) plays a critical role in satiety and energy homeostasis, and its dysregulation is implicated in numerous hyperphagic and obese disease states. Setmelanotide, a disulfide-based cyclic peptide, can rescue MC4R activity and treat obesities caused by genetic defects in MC4R signaling. But this peptide has moderate blood–brain barrier penetrance and metabolic stability, which can limit its efficacy in practice. Based on the cryo-electron microscopy structure of setmelanotide-bound MC4R, we hypothesized that replacing its lone disulfide bond with more metabolically stable and permeability-enhancing carbon-based linker groups could improve pharmacokinetic properties without abolishing activity. To test this, we used chemistry developed by our lab to prepare 11 carbocyclic (alkyl, aryl, perfluoroalkyl, and ethereal) analogs of setmelanotide and determined their biochemical potencies at MC4R in vitro. Ten analogs displayed full agonism, showing that disulfide replacement is tolerant of linkers ranging in size, rigidity, and functional groups, with heteroatom- or aryl-rich linkers displaying superior potencies.
