Gary Samuel, Roy Anuradha, Bloom Steven
Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas, USA.
High Throughput Screening Laboratory, University of Kansas, Lawrence, Kansas, USA.
J Pept Sci. 2025 Feb;31(2):e3656. doi: 10.1002/psc.3656. Epub 2024 Oct 12.
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.
黑皮质素4受体（MC4R）在饱腹感和能量稳态中起关键作用，其功能失调与多种食欲亢进和肥胖疾病状态有关。Setmelanotide是一种基于二硫键的环肽，可恢复MC4R活性并治疗由MC4R信号通路遗传缺陷引起的肥胖症。但这种肽具有中等的血脑屏障穿透性和代谢稳定性，这可能会限制其在实际应用中的疗效。基于与Setmelanotide结合的MC4R的冷冻电子显微镜结构，我们推测用代谢更稳定且能增强通透性的碳基连接基团取代其唯一的二硫键，可以改善药代动力学性质而不消除活性。为了验证这一点，我们利用实验室开发的化学方法制备了11种Setmelanotide的碳环（烷基、芳基、全氟烷基和醚类）类似物，并在体外测定了它们对MC4R的生化活性。十种类似物表现出完全激动作用，表明二硫键取代对大小、刚性和官能团各异的连接基团具有耐受性，富含杂原子或芳基的连接基团表现出更高的活性。
