TY - JOUR
T1 - Structure-Based Design of Melanocortin 4 Receptor Ligands Based on the SHU-9119-hMC4R Cocrystal Structure †
AU - Martin, Charlotte
AU - Gimenez, Luis E.
AU - Williams, Savannah Y.
AU - Jing, Yu
AU - Wu, Yiran
AU - Hollanders, Charlie
AU - Van Der Poorten, Olivier
AU - Gonzalez, Simon
AU - Van Holsbeeck, Kevin
AU - Previti, Santo
AU - Lamouroux, Arthur
AU - Zhao, Suwen
AU - Tourwé, Dirk
AU - Stevens, Raymond C.
AU - Cone, Roger D.
AU - Ballet, Steven
N1 - Funding Information:
C.M., D.T., and S.B. thank the Spearhead (SRP) program of the Vrije Universiteit Brussel for the financial support. K.V.h. and S.B. acknowledge the Research Foundation Flanders (FWO Vlaanderen) for providing a PhD fellowship to K.V.h. S.Z. thanks the National Natural Science Foundation of China grant 31971178. R.D.C. was supported by NIHRO1 DK070332.
Publisher Copyright:
© 2020 American Chemical Society.
PY - 2021/1/14
Y1 - 2021/1/14
N2 - The melanocortin receptors (MC1R-MC5R) belong to class A G-protein-coupled receptors (GPCRs) and are known to have receptor-specific roles in normal and diseased states. Selectivity for MC4R is of particular interest due to its involvement in various metabolic disorders, including obesity, feeding regulation, and sexual dysfunctions. To further improve the potency and selectivity of MC4R (ant)agonist peptide ligands, we designed and synthesized a series of cyclic peptides based on the recent crystal structure of MC4R in complex with the well-characterized antagonist SHU-9119 (Ac-Nle4-c[Asp5-His6-DNal(2′)7-Arg8-Trp9-Lys10]-NH2). These analogues were pharmacologically characterized in vitro, giving key insights into exploiting binding site subpockets to deliver more selective ligands. More specifically, the side chains of the Nle4, DNal(2′)7, and Trp9 residues in SHU-9119, as well as the amide linkage between the Asp5 and Lys10 side chains, were found to represent structural features engaging a hMC4R/hMC3R selectivity switch.
AB - The melanocortin receptors (MC1R-MC5R) belong to class A G-protein-coupled receptors (GPCRs) and are known to have receptor-specific roles in normal and diseased states. Selectivity for MC4R is of particular interest due to its involvement in various metabolic disorders, including obesity, feeding regulation, and sexual dysfunctions. To further improve the potency and selectivity of MC4R (ant)agonist peptide ligands, we designed and synthesized a series of cyclic peptides based on the recent crystal structure of MC4R in complex with the well-characterized antagonist SHU-9119 (Ac-Nle4-c[Asp5-His6-DNal(2′)7-Arg8-Trp9-Lys10]-NH2). These analogues were pharmacologically characterized in vitro, giving key insights into exploiting binding site subpockets to deliver more selective ligands. More specifically, the side chains of the Nle4, DNal(2′)7, and Trp9 residues in SHU-9119, as well as the amide linkage between the Asp5 and Lys10 side chains, were found to represent structural features engaging a hMC4R/hMC3R selectivity switch.
UR - http://www.scopus.com/inward/record.url?scp=85096535520&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.0c01620
DO - 10.1021/acs.jmedchem.0c01620
M3 - Article
C2 - 33190475
AN - SCOPUS:85096535520
SN - 0022-2623
VL - 64
SP - 357
EP - 369
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 1
ER -