Truncation Studies of ?-Melanotropin Peptides Identify Tripeptide Analogues Exhibiting Prolonged Agonist Bioactivity

Haskell‐Luevano, Carrie; Sawyer, Tomi K.; Hendrata, Siska; North, Cheryl; Panahinia, Laila; Stum, Martha; Staples, Douglas J.; Castrucci, A. M. De L.; Hadley, Mac E.; Hruby, Victor J.

doi:10.1016/s0196-9781(96)00141-6

Cited by 44 publications

(54 citation statements)

References 36 publications

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“…This report extends previous structure-activity studies focused on the active site of the melanocortin agonist ligands [9][10][11]20 by performing a comprehensive structurefunction study of the melanocortin agonist NDP-MSH peptide fragments at the MC1, MC3, MC4, and MC5 melanocortin receptors. The most noteworthy results of this study are that the NDP-MSH based tetrapeptide contains nanomolar agonist activities at the mouse MC1 (25.6 nM EC 50 ), MC4 (10.2 nM EC 50 ), and MC5 (3.5 nM EC 50 ) receptors ( Figure 1).…”

Section: Discussionsupporting

confidence: 64%

“…All these melanocortin peptide agonists contain a core His-Phe-Arg-Trp tetrapeptide sequence that has been attributed to the ligand selectivity and stimulation of the melanocortin receptors. [9][10][11] The melanocortin receptor family also has two endogenous antagonists, agouti 12 and the agouti-related protein (AGRP), 13,14 which are the only known antagonists of GPCR's discovered to date.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of Melanocortin NDP-MSH Agonist Peptide Fragments at the Mouse Central and Peripheral Melanocortin Receptors

et al. 2001

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The central melanocortin receptors, melanocortin-4 (MC4R) and melanocortin-3 (MC3R), are involved in the regulation of satiety and energy homeostasis. The MC4R in particular has become a pharmaceutical industry drug target due to its direct involvement in the regulation of food intake and its potential therapeutic application for the treatment of obesity-related diseases. The melanocortin receptors are stimulated by the native ligand, alpha-melanocyte stimulating hormone (alpha-MSH). The potent and enzymatically stable analogue NDP-MSH (Ac-Ser-Tyr-Ser-Nle-Glu-His-DPhe-Arg-Trp-Gly-Lys-Pro-Val-NH(2)) is a lead peptide for the identification of melanocortin amino acids important for receptor molecular recognition and stimulation. We have synthesized nine peptide fragments of NDP-MSH, deleting N- and C-terminal amino acids to determine the "minimally active" sequence of NDP-MSH. Additionally, five peptides were synthesized to study stereochemical inversion at the Phe 7 and Trp 9 positions in attempts to increase tetra- and tripeptide potencies. These peptide analogues were pharmacologically characterized at the mouse melanocortin MC1, MC3, MC4, and MC5 receptors. This study has identified the Ac-His-DPhe-Arg-Trp-NH(2) tetrapeptide as possessing 10 nM agonist activity at the brain MC4R. The tripeptide Ac-DPhe-Arg-Trp-NH(2) possessed micromolar agonist activities at the MC1R, MC4R, and MC5R but only slight stimulatory activity was observed at the MC3R (at up to 100 microM concentration). This study has also examined to importance of both N- and C-terminal NDP-MSH amino acids at the different melanocortin receptors, providing information for drug design and identification of putative ligand-receptor interactions.

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Section: Discussionsupporting

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Characterization of Melanocortin NDP-MSH Agonist Peptide Fragments at the Mouse Central and Peripheral Melanocortin Receptors

et al. 2001

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“…Much is known about the structure-activity relationships of NDP--MSH [6,7] and ligand-receptor interactions involving hMC4R [8]. In addition, it has been shown that the N-terminal tripeptide of NDP--MSH is not required to maintain high potency, thereby providing a suitable site for conjugate attachment [9][10][11].…”

Section: Design and Synthesis Of Xuorescent Lanthanide Chelatesmentioning

confidence: 99%

Lanthanide-based time-resolved fluorescence of in cyto ligand–receptor interactions

Handl

Vagner

Yamamura

et al. 2004

Analytical Biochemistry

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“…ACTH is the only known endogenous agonist at MC2R, whereas ACTH as well as α-, β-, and γ-MSH bind to other MCRs (2, 4, 11-13, 48, 54, 55, 57). All melanocortins have a shared core amino acid sequence, His-Phe-Arg-Trp (HFRW), which is critical for melanocortin binding and signaling (27,28,47). In this study, both truncated ACTH peptides and site-directed mutagenesis studies were utilized to determine the molecular basis of MC2R responsible for ACTH binding and signaling.…”

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confidence: 99%

Molecular Identification of the Human Melanocortin-2 Receptor Responsible for Ligand Binding and Signaling

et al. 2007

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The melanocortin-2 receptor (MC2R), also known as the adrenocorticotropic hormone (ACTH) receptor, plays an important role in regulating and maintaining adrenocortical function, specifically steroidogenesis. Mutations of the MC2R gene have also been identified in humans with familial glucocorticoid deficiency. However, the molecular basis of MC2R responsible for ligand binding and signaling remains unclear. In this study, both truncated ACTH peptides and site-directed mutagenesis studies were utilized to determine the molecular basis of MC2R responsible for ACTH binding and signaling. Our results indicate that ACTH1-16 is the minimal peptide required for MC2R binding and signaling and mutations of the conserved amino acid residues E80 in transmembrane domain 2 (TM2), D107 in TM3, F178 in TM4, F235, H238 in TM6 and F258 in TM7 significantly reduced ACTH binding affinity and signaling, which is similar to other MCRs. Furthermore, mutations of unique amino acids D104 and F108 in TM3, and F168 and F178 in TM4, significantly decreased ACTH binding and signaling. In conclusion, our results suggest that the residues in TM2, TM3 and TM6 of hMC2R share similar binding sites with other MCRs but the residues identified in TM4, TM7 of hMC2R are unique for ACTH binding. Our study suggests that hMC2R may have a broad binding pocket in which both conserved and unique amino acid residues are involved, which may be the reason why α-MSH was not able to bind hMC2R. Keywords stress; POMC; MC2R; agonist; GPCR The melanocortin-2 receptor (MC2R), also known as the adrenocorticotropic hormone (ACTH) receptor, plays an important role in the regulation of adrenal cortisol secretion (9). Mutations of the hMC2R have been identified in a potentially fatal disease called familial glucocorticoid deficiency (FGD) in which affected individuals are deficient in cortisol and likely to succumb to hypoglycemia or overwhelming infection in infancy or childhood if they are not treated (8,10,16,35,39,40,44,49,50,52,(58)(59)(60). Over expression of this receptor is also found in adrenal adenomas or hyperplasia associated with glucocorticoid overproduction (Cushing syndrome) (1,22,37,38).Extensive studies had been performed to determine the molecular basis of ACTH in receptor function in the last two decades but the results are not consistent. In early years, ACTH1-14, ACTH11-19 and ACTH11-24 were reported to increase corticosterone levels in the isolated adrenal cell system and ACTH11-24 plays an important role in adipocyte function (14,24,42,45). However, ACTH1-14 was also reported not able to bind MC2R (48). The explanation for these variations is that different methods of adrenal cell preparation and separate receptors may be involved in these peptide activities (53). Further studies of some ACTH peptide truncations indicated that ACTH1-17 is the minimal peptide required for ligand binding and signaling (14,24,42,45). However, detailed structure-function of ACTH responsible for MC2R binding and signaling is still unclear.Cloning of melanoco...

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Truncation Studies of ?-Melanotropin Peptides Identify Tripeptide Analogues Exhibiting Prolonged Agonist Bioactivity

Cited by 44 publications

References 36 publications

Characterization of Melanocortin NDP-MSH Agonist Peptide Fragments at the Mouse Central and Peripheral Melanocortin Receptors

Characterization of Melanocortin NDP-MSH Agonist Peptide Fragments at the Mouse Central and Peripheral Melanocortin Receptors

Lanthanide-based time-resolved fluorescence of in cyto ligand–receptor interactions

Molecular Identification of the Human Melanocortin-2 Receptor Responsible for Ligand Binding and Signaling

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