Structure–activity studies of new melanocortin peptides containing an aromatic amino acid at the N-terminal position

Grieco, Paolo; Cai, Minying; Mayorov, Alexander V.; Trivedi, Dev; Hruby, Victor J.

doi:10.1016/j.peptides.2005.01.032

Cited by 11 publications

(12 citation statements)

References 41 publications

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“…It is noteworthy that protein hot-spots relevant as therapeutic targets are frequently localized in Trp-rich β -hairpin regions [ 21 ]. Residues of Trp in the AA sequence of small bioactive peptides, as endogenous anti-inflammatory/antiobesity melanocortin peptides or defense antimicrobial peptides of innate immunity [ 22 , 23 ], need to be further explored in the field of peptides' structure-activity relationships.…”

Section: Tryptophan Residues In Proteins and Peptidesmentioning

confidence: 99%

Tryptophan Biochemistry: Structural, Nutritional, Metabolic, and Medical Aspects in Humans

Palego

Betti

Rossi

et al. 2016

Journal of Amino Acids

240

202

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L-Tryptophan is the unique protein amino acid (AA) bearing an indole ring: its biotransformation in living organisms contributes either to keeping this chemical group in cells and tissues or to breaking it, by generating in both cases a variety of bioactive molecules. Investigations on the biology of Trp highlight the pleiotropic effects of its small derivatives on homeostasis processes. In addition to protein turn-over, in humans the pathways of Trp indole derivatives cover the synthesis of the neurotransmitter/hormone serotonin (5-HT), the pineal gland melatonin (MLT), and the trace amine tryptamine. The breakdown of the Trp indole ring defines instead the “kynurenine shunt” which produces cell-response adapters as L-kynurenine, kynurenic and quinolinic acids, or the coenzyme nicotinamide adenine dinucleotide (NAD+). This review aims therefore at tracing a “map” of the main molecular effectors in human tryptophan (Trp) research, starting from the chemistry of this AA, dealing then with its biosphere distribution and nutritional value for humans, also focusing on some proteins responsible for its tissue-dependent uptake and biotransformation. We will thus underscore the role of Trp biochemistry in the pathogenesis of human complex diseases/syndromes primarily involving the gut, neuroimmunoendocrine/stress responses, and the CNS, supporting the use of -Omics approaches in this field.

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Section: Tryptophan Residues In Proteins and Peptidesmentioning

confidence: 99%

Tryptophan Biochemistry: Structural, Nutritional, Metabolic, and Medical Aspects in Humans

Palego

Betti

Rossi

et al. 2016

Journal of Amino Acids

240

202

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“…Previous reports from our laboratories (23–28) had focused on finding potent and selective agonists and antagonists for the hMC3R and hMC4R, which have been implicated to play complementary roles in weight control (11–17). Recently, Kavarana et al.…”

mentioning

confidence: 99%

Effects of Macrocycle Size and Rigidity on Melanocortin Receptor‐1 and ‐5 Selectivity in Cyclic Lactam α‐Melanocyte‐Stimulating Hormone Analogs

Mayorov

Han²,

Cai

et al. 2006

Chem Biol Drug Des

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The effects of the linker arm rigidity and size on melanocortin receptor selectivity were explored in a series of compounds using cyclic lactam a-melanocyte-stimulating hormone template. A variety of dicarboxylic acid linkers introduced between the a-amino group of His 6 and the e-amino group of Lys 10 lead to high-affinity, selective human melanocortin receptor-1 and -5 (hMC1R and hMC5R) antagonists. The incorporation of hydrophilic functions into the linker arm was found to be unfavorable for both binding potency and receptor selectivity. Analogs 8 and 9 containing highly conformationally constrained hydrophobic linkers (m-and p-phthalic acids) were found to be selective nanomolar range hMC1R antagonists (IC 50 ¼ 7 and 4 nM, respectively), whereas the employment of a small conformationally constrained linker (maleic acid) resulted in a high-affinity (IC 50 ¼ 19 nM) and selective hMC5R antagonist (analog 12). These newly developed melanotropins will serve as critical biochemical tools for elucidating the full spectrum of functions performed by the physiologically important melanocortin-1 and -5 receptors.Key words: a-melanocyte-stimulating hormone, antagonist, human melanocortin-1 receptor, human melanocortin-5 receptor, macrocyclic, melanocortin, peptide Abbreviations: Abbreviations used for amino acids and designation of peptides follow the rules of the IUPAC-IUB Commission of Biochemical Nomenclature in J. Biol. Chem. 1972, 247, 977-983. The following additional abbreviations are used: All, allyl; Alloc, allyloxycarbonyl; Boc, tert-butyloxycarbonyl; Fmoc, fluorenylmethoxycarbonyl; CH 3 CN, acetonitrile; DCM, dichloromethane; DIPEA, diisopropylethylamine; DMF, N,N-dimethylformamide; DIC, diisopropyl carbodiimide; HBTU, 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; HOBt, N-hydroxybenzotriazole; hMCR, human melanocortin receptor; MSH, melanocytestimulating hormone; Nal(2¢), 2¢-naphthylalanine; Pbf, 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl; PyBOP, benzotriazol-1-yloxy-tris-pyrrolidinophosphonium hexafluorophosphate; TFA, trifluoroacetic acid; Trt, trityl; SPPS, solid-phase peptide synthesis; RP-HPLC, reverse-phase highperformance liquid chromatography; hMC1R, human melanocortin-1 receptor; a-MSH, Ac-SerTyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH 2 ; NDP-a-MSH, Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-ArgTrp-Gly-Lys-Pro-Val-NH 2 . Received 6 April 2006, revised 25 April 2006 and accepted for publication 26 April 2006The natural melanocortin agonists, a-, b-, c-melanocyte-stimulating hormones (MSHs), and adrenocorticotropin have been receiving great attention in the recent years because of their involvement in a large number of multifaceted biological actions, including skin pigmentation (1-3), control of the immune system (1-4), erectile function (5-9), blood pressure and heart rate (10), control of feeding behavior and energy homeostasis (11-17), modulation of aggressive/defensive behavior (18), and mediation of pain (19). These endogenous neuropeptides are ligands for the fiv...

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“…In the meantime, B. Kest and colleagues (Juni et al, 2010) have shown that this ligand can modulate hyperalgesia in a gender specific manner. An analogue of Ac-Nle 4 -c[Asp 5 ,D-Phe 7 ,Lys 10 ]-α-MSH(4-10)-NH 2 in which the Nle 4 residue is replaced by a D-Phe and the His 6 residue by a Pro residue ( 3 , Table 1) (Grieco et al, 2006) gave a ligand that was more selective as an human melanocortin MC 3 receptor agonist than [D-Trp 8 ] γ-melanocyte stimulating hormone (Grieco et al, 2000) since it had antagonist activities at both the human melanocortin MC 4 receptor and human melanocortin MC 5 receptor. A very interesting and unique conformationally and topographically constrained analogue 4 (Table 1) was examined for its biological activity profile.…”

Section: Resultsmentioning

confidence: 99%

Design of novel melanocortin receptor ligands: Multiple receptors, complex pharmacology, the challenge

Hruby

Cai

Cain

et al. 2011

European Journal of Pharmacology

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The major pharmacophore for the melanocortin 1,3,4 and 5 receptors is the sequence -His-Phe-Arg-Trp-. There is a need for potent, biologically stable, receptor selective ligands, both agonists and antagonists, for these receptors. In this report we briefly examine the structural and biophysical approaches we have taken to develop selective agonist and antagonist ligands that can cross (or not) the blood brain barrier. Remaining questions and unmet needs are also discussed.

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Structure–activity studies of new melanocortin peptides containing an aromatic amino acid at the N-terminal position

Cited by 11 publications

References 41 publications

Tryptophan Biochemistry: Structural, Nutritional, Metabolic, and Medical Aspects in Humans

Tryptophan Biochemistry: Structural, Nutritional, Metabolic, and Medical Aspects in Humans

Effects of Macrocycle Size and Rigidity on Melanocortin Receptor‐1 and ‐5 Selectivity in Cyclic Lactam α‐Melanocyte‐Stimulating Hormone Analogs

Design of novel melanocortin receptor ligands: Multiple receptors, complex pharmacology, the challenge

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