Luis E Gimenez, Charlotte Martin, Jing Yu, Charlie Hollanders, Ciria C Hernandez, Yiran Wu, Deqiang Yao, Gye Won Han, Naima S Dahir, Lijie Wu, Olivier Van der Poorten, Arthur Lamouroux, Morgane Mannes, Suwen Zhao, Dirk Tourwé, Raymond C Stevens, Roger D Cone, Steven Ballet
Melanocortin 4 receptor (MC4-R) antagonists are actively sought for treating cancer cachexia. We determined the structures of complexes with PG-934 and SBL-MC-31 . These peptides differ from SHU9119 by substituting His6 with Pro6 and inserting Gly10 or Arg10 . The structures revealed two subpockets at the TM7-TM1-TM2 domains, separated by N2857.36 . Two peptide series based on the complexed peptides led to an antagonist activity and selectivity SAR study. Most ligands retained the SHU9119 potency, but several SBL-MC-31 -derived peptides significantly enhanced MC4-R selectivity over MC1-R by 60- to 132-fold...
February 12, 2024: Journal of Medicinal Chemistry