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

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2021 Oct 1

PMID 34592820

Citations 5

Authors

Mark D Ericson

Skye R Doering

Courtney M Larson

Katie T Freeman

Travis M Lavoi

Haley M Donow

Radleigh G Santos

Rachel H Cho

Zoe M Koerperich

Marc A Giulianotti

Clemencia Pinilla

Richard A Houghten

Carrie Haskell-Luevano

Affiliations

Soon will be listed here.

Abstract

The melanocortin-4 receptor (MC4R) plays an important role in appetite. Agonist ligands that stimulate the MC4R decrease appetite, while antagonist compounds increase food consumption. Herein, a functional mixture-based positional scan identified novel MC4R antagonist sequences. Mixtures comprising a library of 12,960,000 tetrapeptides were screened in the presence and absence of the NDP-MSH agonist. These results led to the synthesis of 48 individual tetrapeptides, of which 40 were screened for functional activity at the melanocortin receptors. Thirteen compounds were found to possess nanomolar antagonist potency at the MC4R, with the general tetrapeptide sequence Ac-Aromatic-Basic-Aromatic-Basic-NH. The most notable results include the identification of tetrapeptide [, Ac-DPhe(pI)-Arg-Nal(2')-Arg-NH], an equipotent MC4R antagonist to agouti-related protein [AGRP(86-132)], more potent than miniAGRP(87-120), and possessing 15-fold selectivity for the MC4R versus the MC3R. These tetrapeptides may serve as leads for novel appetite-inducing therapies to treat states of negative energy balance, such as cachexia and anorexia.

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References

Clement K, Biebermann H, Farooqi I, van der Ploeg L, Wolters B, Poitou C . MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency. Nat Med. 2018; 24(5):551-555. DOI: 10.1038/s41591-018-0015-9. View

Haslach E, Huang H, Dirain M, Debevec G, Geer P, Santos R . 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). J Med Chem. 2014; 57(11):4615-28. PMC: 4324447. DOI: 10.1021/jm500064t. View

Adank D, Lunzer M, Lensing C, Wilber S, Gancarz A, Haskell-Luevano C . Comparative in Vivo Investigation of Intrathecal and Intracerebroventricular Administration with Melanocortin Ligands MTII and AGRP into Mice. ACS Chem Neurosci. 2017; 9(2):320-327. PMC: 5821609. DOI: 10.1021/acschemneuro.7b00330. View

Fleming K, Freeman K, Powers M, Santos R, Debevec G, Giulianotti M . 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. J Med Chem. 2019; 62(5):2738-2749. PMC: 6463894. DOI: 10.1021/acs.jmedchem.9b00053. View

Kim J, Seok J, Kim Y, Boo Y . Identification of small peptides and glycinamide that inhibit melanin synthesis using a positional scanning synthetic peptide combinatorial library. Br J Dermatol. 2019; 181(1):128-137. DOI: 10.1111/bjd.17634. View

Kaiser E, Colescott R, Bossinger C, Cook P . Color test for detection of free terminal amino groups in the solid-phase synthesis of peptides. Anal Biochem. 1970; 34(2):595-8. DOI: 10.1016/0003-2697(70)90146-6. View

Pinilla C, Appel J, Borras E, Houghten R . Advances in the use of synthetic combinatorial chemistry: mixture-based libraries. Nat Med. 2003; 9(1):118-22. DOI: 10.1038/nm0103-118. View

Tala S, Schnell S, Haskell-Luevano C . Microwave-assisted solid-phase synthesis of side-chain to side-chain lactam-bridge cyclic peptides. Bioorg Med Chem Lett. 2015; 25(24):5708-11. PMC: 4654418. DOI: 10.1016/j.bmcl.2015.10.095. View

Yeo G, Farooqi I, Aminian S, Halsall D, Stanhope R, ORahilly S . A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet. 1998; 20(2):111-2. DOI: 10.1038/2404. View

10.

Gantz I, Konda Y, Tashiro T, Shimoto Y, Miwa H, Munzert G . Molecular cloning of a novel melanocortin receptor. J Biol Chem. 1993; 268(11):8246-50. View

11.

Doering S, Freeman K, Schnell S, Haslach E, Dirain M, Debevec G . Discovery of Mixed Pharmacology Melanocortin-3 Agonists and Melanocortin-4 Receptor Tetrapeptide Antagonist Compounds (TACOs) Based on the Sequence Ac-Xaa-Arg-(pI)DPhe-Xaa-NH. J Med Chem. 2017; 60(10):4342-4357. PMC: 5672800. DOI: 10.1021/acs.jmedchem.7b00301. View

12.

Ericson M, Freeman K, Schnell S, Fleming K, Haskell-Luevano C . Structure-Activity Relationship Studies on a Macrocyclic Agouti-Related Protein (AGRP) Scaffold Reveal Agouti Signaling Protein (ASP) Residue Substitutions Maintain Melanocortin-4 Receptor Antagonist Potency and Result in Inverse Agonist.... J Med Chem. 2017; 60(19):8103-8114. PMC: 5645029. DOI: 10.1021/acs.jmedchem.7b00856. View

13.

Grieco P, Lavecchia A, Cai M, Trivedi D, Weinberg D, MacNeil T . Structure-activity studies of the melanocortin peptides: discovery of potent and selective affinity antagonists for the hMC3 and hMC4 receptors. J Med Chem. 2002; 45(24):5287-94. DOI: 10.1021/jm0202526. View

14.

Clement K, van den Akker E, Argente J, Bahm A, Chung W, Connors H . Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials. Lancet Diabetes Endocrinol. 2020; 8(12):960-970. DOI: 10.1016/S2213-8587(20)30364-8. View

15.

Nakanishi S, Inoue A, Kita T, Nakamura M, Chang A, Cohen S . Nucleotide sequence of cloned cDNA for bovine corticotropin-beta-lipotropin precursor. Nature. 1979; 278(5703):423-7. DOI: 10.1038/278423a0. View

16.

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

17.

Ericson M, Haslach E, Schnell S, Freeman K, Xiang Z, Portillo F . Discovery of Molecular Interactions of the Human Melanocortin-4 Receptor (hMC4R) Asp189 (D189) Amino Acid with the Endogenous G-Protein-Coupled Receptor (GPCR) Antagonist Agouti-Related Protein (AGRP) Provides Insights to AGRP's Inverse Agonist.... ACS Chem Neurosci. 2021; 12(3):542-556. PMC: 7951137. DOI: 10.1021/acschemneuro.0c00755. View

18.

Ericson M, Wilczynski A, Sorensen N, Xiang Z, Haskell-Luevano C . Discovery of a β-Hairpin Octapeptide, c[Pro-Arg-Phe-Phe-Dap-Ala-Phe-DPro], Mimetic of Agouti-Related Protein(87-132) [AGRP(87-132)] with Equipotent Mouse Melanocortin-4 Receptor (mMC4R) Antagonist Pharmacology. J Med Chem. 2015; 58(11):4638-47. PMC: 5672791. DOI: 10.1021/acs.jmedchem.5b00184. View

19.

Haskell-Luevano C, Holder J, Monck E, Bauzo R . Characterization of melanocortin NDP-MSH agonist peptide fragments at the mouse central and peripheral melanocortin receptors. J Med Chem. 2001; 44(13):2247-52. DOI: 10.1021/jm010061n. View

20.

HAYNES Jr R . The activation of adrenal phosphorylase by the adrenocorticotropic hormone. J Biol Chem. 1958; 233(5):1220-2. View