Identification of Tetrapeptides from a Mixture Based Positional Scanning Library That Can Restore NM Full Agonist Function of the L106P, I69T, I102S, A219V, C271Y, and C271R Human Melanocortin-4 Polymorphic Receptors (hMC4Rs)

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2014 Feb 13

PMID 24517312

Citations 11

Authors

Erica M Haslach

Huisuo Huang

Marvin Dirain

Ginamarie Debevec

Phaedra Geer

Radleigh G Santos

Marc A Giulianotti

Clemencia Pinilla

Jon R Appel

Skye R Doering

Michael A Walters

Richard A Houghten

Carrie Haskell-Luevano

Affiliations

Soon will be listed here.

Abstract

Human obesity has been linked to genetic factors and single nucleotide polymorphisms (SNPs). Melanocortin-4 receptor (MC4R) SNPs have been associated with up to 6% frequency in morbidly obese children and adults. A potential therapy for individuals possessing such genetic modifications is the identification of molecules that can restore proper receptor signaling and function. These compounds could serve as personalized medications improving quality of life issues as well as alleviating diseases symptoms associated with obesity including type 2 diabetes. Several hMC4 SNP receptors have been pharmacologically characterized in vitro to have a decreased, or a lack of response, to endogenous agonists such as α-, β-, and γ2-melanocyte stimulating hormones (MSH) and adrenocorticotropin hormone (ACTH). Herein we report the use of a mixture based positional scanning combinatorial tetrapeptide library to discover molecules with nM full agonist potency and efficacy to the L106P, I69T, I102S, A219V, C271Y, and C271R hMC4Rs. The most potent compounds at all these hMC4R SNPs include Ac-His-(pI)DPhe-Tic-(pNO2)DPhe-NH2, Ac-His-(pCl)DPhe-Tic-(pNO2)DPhe-NH2, Ac-His-(pCl)DPhe-Arg-(pI)Phe-NH2, and Ac-Arg-(pCl)DPhe-Tic-(pNO2)DPhe-NH2, revealing new ligand pharmacophore models for melanocortin receptor drug design strategies.

Citing Articles

The Parallel Structure-Activity Relationship Screening of Three Compounds Identifies the Common Agonist Pharmacophore of Pyrrolidine Bis-Cyclic Guanidine Melanocortin-3 Receptor (MC3R) Small-Molecule Ligands.

Ericson M, Freeman K, Lavoi T, Donow H, Santos R, Giulianotti M Int J Mol Sci. 2023; 24(12).

PMID: 37373293 PMC: 10299128. DOI: 10.3390/ijms241210145.

Melanocortin-4 receptor complexity in energy homeostasis,obesity and drug development strategies.

Fatima M, Ahmed I, Fakhro K, Al-Shabeeb Akil A Diabetes Obes Metab. 2021; 24(4):583-598.

PMID: 34882941 PMC: 9302617. DOI: 10.1111/dom.14618.

Functional Mixture-Based Positional Scan Identifies a Library of Antagonist Tetrapeptide Sequences (LAtTeS) with Nanomolar Potency for the Melanocortin-4 Receptor and Equipotent with the Endogenous AGRP(86-132) Antagonist.

Ericson M, Doering S, Larson C, Freeman K, Lavoi T, Donow H J Med Chem. 2021; 64(19):14860-14875.

PMID: 34592820 PMC: 8533642. DOI: 10.1021/acs.jmedchem.1c01417.

Discovery of Nanomolar Melanocortin-3 Receptor (MC3R)-Selective Small Molecule Pyrrolidine Bis-Cyclic Guanidine Agonist Compounds Via a High-Throughput "Unbiased" Screening Campaign.

Doering S, Freeman K, Debevec G, Geer P, Santos R, Lavoi T J Med Chem. 2021; 64(9):5577-5592.

PMID: 33886285 PMC: 8552302. DOI: 10.1021/acs.jmedchem.0c02041.

Discovery of Polypharmacological Melanocortin-3 and -4 Receptor Probes and Identification of a 100-Fold Selective nM MC3R Agonist versus a μM MC4R Partial Agonist.

Fleming K, Freeman K, Powers M, Santos R, Debevec G, Giulianotti M J Med Chem. 2019; 62(5):2738-2749.

PMID: 30741545 PMC: 6463894. DOI: 10.1021/acs.jmedchem.9b00053.

References

Dooley C, Ny P, Bidlack J, Houghten R . Selective ligands for the mu, delta, and kappa opioid receptors identified from a single mixture based tetrapeptide positional scanning combinatorial library. J Biol Chem. 1998; 273(30):18848-56. DOI: 10.1074/jbc.273.30.18848. View

Wilczynski A, Wilson K, Scott J, Edison A, Haskell-Luevano C . Structure-activity relationships of the unique and potent agouti-related protein (AGRP)-melanocortin chimeric Tyr-c[beta-Asp-His-DPhe-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH2 peptide template. J Med Chem. 2005; 48(8):3060-75. DOI: 10.1021/jm049010r. View

Xiang Z, Proneth B, Dirain M, Litherland S, Haskell-Luevano C . Pharmacological characterization of 30 human melanocortin-4 receptor polymorphisms with the endogenous proopiomelanocortin-derived agonists, synthetic agonists, and the endogenous agouti-related protein antagonist. Biochemistry. 2010; 49(22):4583-600. PMC: 2888279. DOI: 10.1021/bi100068u. View

Castrucci A, Hadley M, Hruby V . Potent and prolonged acting cyclic lactam analogues of alpha-melanotropin: design based on molecular dynamics. J Med Chem. 1989; 32(12):2555-61. DOI: 10.1021/jm00132a010. View

Grieco P, Balse P, Weinberg D, MacNeil T, Hruby V . D-Amino acid scan of gamma-melanocyte-stimulating hormone: importance of Trp(8) on human MC3 receptor selectivity. J Med Chem. 2001; 43(26):4998-5002. DOI: 10.1021/jm000211e. View

Grieco P, Balse-Srinivasan P, Han G, Weinberg D, MacNeil T, van der Ploeg L . Synthesis and biological evaluation on hMC3, hMC4 and hMC5 receptors of gamma-MSH analogs substituted with L-alanine. J Pept Res. 2002; 59(5):203-10. DOI: 10.1034/j.1399-3011.2002.01966.x. View

Willer C, Speliotes E, Loos R, Li S, Lindgren C, Heid I . Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet. 2008; 41(1):25-34. PMC: 2695662. DOI: 10.1038/ng.287. View

Hogan K, Peluso S, Gould S, Parsons I, Ryan D, Wu L . Mapping the binding site of melanocortin 4 receptor agonists: a hydrophobic pocket formed by I3.28(125), I3.32(129), and I7.42(291) is critical for receptor activation. J Med Chem. 2006; 49(3):911-22. DOI: 10.1021/jm050780s. View

Chai B, Pogozheva I, Lai Y, Li J, Neubig R, Mosberg H . Receptor-antagonist interactions in the complexes of agouti and agouti-related protein with human melanocortin 1 and 4 receptors. Biochemistry. 2005; 44(9):3418-31. DOI: 10.1021/bi0478704. View

10.

Holder J, Bauzo R, Xiang Z, Haskell-Luevano C . Structure-activity relationships of the melanocortin tetrapeptide Ac-His-DPhe-Arg-Trp-NH(2) at the mouse melanocortin receptors. 1. Modifications at the His position. J Med Chem. 2002; 45(13):2801-10. DOI: 10.1021/jm0104872. View

11.

Houghten R, Pinilla C, Giulianotti M, Appel J, Dooley C, Nefzi A . Strategies for the use of mixture-based synthetic combinatorial libraries: scaffold ranking, direct testing in vivo, and enhanced deconvolution by computational methods. J Comb Chem. 2007; 10(1):3-19. DOI: 10.1021/cc7001205. View

12.

Dubern B, Clement K, Pelloux V, Froguel P, Girardet J, Guy-Grand B . Mutational analysis of melanocortin-4 receptor, agouti-related protein, and alpha-melanocyte-stimulating hormone genes in severely obese children. J Pediatr. 2001; 139(2):204-9. DOI: 10.1067/mpd.2001.116284. View

13.

Atalayer D, Robertson K, Haskell-Luevano C, Andreasen A, Rowland N . Food demand and meal size in mice with single or combined disruption of melanocortin type 3 and 4 receptors. Am J Physiol Regul Integr Comp Physiol. 2010; 298(6):R1667-74. PMC: 2886701. DOI: 10.1152/ajpregu.00562.2009. View

14.

Yang Y, Fong T, Dickinson C, Mao C, Li J, Tota M . Molecular determinants of ligand binding to the human melanocortin-4 receptor. Biochemistry. 2000; 39(48):14900-11. DOI: 10.1021/bi001684q. View

15.

Singh A, Wilczynski A, Holder J, Witek R, Dirain M, Xiang Z . Incorporation of a bioactive reverse-turn heterocycle into a peptide template using solid-phase synthesis to probe melanocortin receptor selectivity and ligand conformations by 2D 1H NMR. J Med Chem. 2011; 54(5):1379-90. PMC: 3076140. DOI: 10.1021/jm101425m. View

16.

Dooley C, Houghten R . The use of positional scanning synthetic peptide combinatorial libraries for the rapid determination of opioid receptor ligands. Life Sci. 1993; 52(18):1509-17. DOI: 10.1016/0024-3205(93)90113-h. View

17.

Farooqi I, Yeo G, Keogh J, Aminian S, Jebb S, Butler G . Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. J Clin Invest. 2000; 106(2):271-9. PMC: 314308. DOI: 10.1172/JCI9397. View

18.

Tao Y, Segaloff D . Functional analyses of melanocortin-4 receptor mutations identified from patients with binge eating disorder and nonobese or obese subjects. J Clin Endocrinol Metab. 2005; 90(10):5632-8. DOI: 10.1210/jc.2005-0519. View

19.

Mountjoy K, Mortrud M, Low M, Simerly R, Cone R . Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol Endocrinol. 1994; 8(10):1298-308. DOI: 10.1210/mend.8.10.7854347. View

20.

Tan K, Pogozheva I, Yeo G, Hadaschik D, Keogh J, Haskell-Leuvano C . Functional characterization and structural modeling of obesity associated mutations in the melanocortin 4 receptor. Endocrinology. 2008; 150(1):114-25. PMC: 2732289. DOI: 10.1210/en.2008-0721. View