Carbocyclic setmelanotide analogs maintain biochemical potency at melanocortin 4 receptors.
carbocyclic peptides
melanocortin 4
obesity
setmelanotide
Journal
Journal of peptide science : an official publication of the European Peptide Society
ISSN: 1099-1387
Titre abrégé: J Pept Sci
Pays: England
ID NLM: 9506309
Informations de publication
Date de publication:
12 Oct 2024
12 Oct 2024
Historique:
revised:
20
09
2024
received:
29
06
2024
accepted:
23
09
2024
medline:
12
10
2024
pubmed:
12
10
2024
entrez:
12
10
2024
Statut:
aheadofprint
Résumé
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.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e3656Subventions
Organisme : School of Pharmacy and University of Kansas Startup
ID : 2506031-099
Organisme : National Institutes of General Medical Sciences
ID : P20GM113117
Organisme : National Institutes of General Medical Sciences
ID : R35GM147169
Organisme : National Institutes of General Medical Sciences
ID : T32GM132061
Informations de copyright
© 2024 European Peptide Society and John Wiley & Sons Ltd.
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