Structure-function studies on the cyclic peptide MT-II, lactam derivative of α-melanotropin

Bednarek, Maria A.; Silva, Maria V.; Arison, Byron H.; MacNeil, Tanya; Kalyani, Rubana N.; Huang, Ruey-Ruey C.; Weinberg, David H.

doi:10.1016/s0196-9781(99)00048-0

Cited by 72 publications

(129 citation statements)

References 31 publications

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“…Also, at the other MC receptors, for example, D-Ala 9 -NDP-aMSH 16 showed the pharmacological profile similar to that of the L-Ala 9 compound (2). The new analog 16 was a 1.2 nM agonist at hMC1bR, a partial weak agonist at hMC3/5R and practically inactive at hMC4R.…”

Section: Analogs Of Amsh (26) and Ndp-amsh (1) Listed Inmentioning

confidence: 76%

“…The same segment was found to be critical to binding and potency of most synthetic, peptidic ligands at the melanocortin receptors. [15][16][17][18][19][20] Hypothetical three-dimensional models of complexes of the melanocortin receptor 1 with aMSH, and its two synthetic analogs NDP-aMSH and MTII, were proposed. [21][22][23][24][25][26] Ac-Ser In some of those mutants, one of the aromatic residues of hMC1R listed above was replaced with Ala, and such single alteration to the structure of hMC1R had a negligible effect on binding affinity and agonism of NDP-aMSH.…”

Section: 13mentioning

confidence: 99%

“…16 Binding data were analyzed using GraphPad curve-fitting software. Active peptides were evaluated in three or more independent experiments.…”

Section: Competitive Binding Assaysmentioning

confidence: 99%

“…16 for details). Cells were detached from tissue culture flasks, collected by 5-min centrifugation, and resuspended in Earle's Balanced Salt solution [Life Technologies, Gaithersburg, molecular dynamics (MD)] with addition of 10 mM HEPES (pH 7.5), 5 mM MgCl 2 , 1 mM glutamine, and 1 mg/ml bovine serum albumin.…”

Section: Camp Assaysmentioning

confidence: 99%

“…Tables I and 2 were prepared by solid phase syntheses as previously described (see Ref. 16 and the Experimental Section.) (Throughout this report, the numbering of the amino acid residues in aMSH, Ac-Ser The human melanocortin 1b receptor (hMC1bR) possesses pharmacological properties virtually identical to that of its isoform, human melanocortin receptor 1a (hMC1aR).…”

Section: Camp Assaysmentioning

confidence: 99%

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Analogs of α‐melanocyte stimulating hormone with high agonist potency and selectivity at human melanocortin receptor 1b: The role of Trp⁹ in molecular recognition

et al. 2007

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Every week for a half an hour, however, he gave undivided attention to each member of his laboratory, his postdoctoral students and visiting scientists. We all looked forward to those brief but so rewarding interactions. He expected us to be independent scientists, concise and clear about what we wanted to accomplish. He discussed our efforts and judgments, provided criticism and reassurance. And all the time we were absolutely in awe of this brilliant scientist, teacher, mentor, manager, statesman and businessman. He was our rock, always calm, friendly, and kind. We felt very fortunate to be part of ERB's world, participate in his research endeavors, and observe his extraordinary interactions with scientists, managers, business people and politicians. It was certainly a unique experience reaching far beyond the typical postdoctoral training. I treasure memories of Dr. Elkan R. Blout from the lab at Harvard Medical School. Equally warmly, I treasure memories of ERB and his family from the lab gatherings at the Harvard and Commonwealth Clubs or at his house.

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Section: Analogs Of Amsh (26) and Ndp-amsh (1) Listed Inmentioning

confidence: 76%

Section: 13mentioning

confidence: 99%

“…16 Binding data were analyzed using GraphPad curve-fitting software. Active peptides were evaluated in three or more independent experiments.…”

Section: Competitive Binding Assaysmentioning

confidence: 99%

Section: Camp Assaysmentioning

confidence: 99%

Section: Camp Assaysmentioning

confidence: 99%

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Analogs of α‐melanocyte stimulating hormone with high agonist potency and selectivity at human melanocortin receptor 1b: The role of Trp⁹ in molecular recognition

et al. 2007

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¹H‐NMR studies on a potent and selective antagonist at human melanocortin receptor 4 (hMC‐4R)

et al. 2003

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Melanocortin receptor 4 (MC-4R) is involved in the regulation of energy balance and body weight, and recognizes alpha-, beta-, and gamma-melanocyte stimulating hormones (alpha-, beta-, gamma-MSH). In the search for compounds that regulate food intake and body weight, two synthetic lactam-derivative ligands of alpha-MSH were discovered, MTII and SHU9119. MTII is an agonist and reduces food intake in rats, whereas SHU9119 is an antagonist, and increases food intake and body weight in rats. MTII and SHU9119 are nonselective compounds to MC-4R. To enhance the potency and selectivity at the human MC-4R (hMC-4R), we recently synthesized analogs of SHU9119 (M. A. Bednarek, T. MacNeil, R. N. Kalyani, R. Tang, Van der L. H. T. Ploeg, and D. H. Weinberg, Journal of Medicinal Chemistry, 2001, Vol. 44, pp. 401-409), wherein compound 1 was the most selective for hMC-4R. Replacement of D-Nal by L-Nal in compound 1 made compound 2 weakly active. Comparison of the structures by NMR and molecular modeling of compounds 1 and 2 vs SHU9119 and MTII indicated that, even though they existed as an average of several conformations in solution, there were distinctions in their structures. The gamma-methylene protons of Arg in compound 1 were nonequivalent and shielded probably by the aromatic ring of Nal. The NHi-NHi+1 NOE cross peaks and the temperature coefficients of the amide protons around the "essential core" Nal/Phe7-Arg8-Trp9, required for high affinity and high selectivity at hMC-4R, were indicative of a possible turn structure for these compounds but with differences in their NOE strengths and temperature coefficient values. Molecular modeling of these compounds based on their NMR data showed that the essential core appeared as a "V" shape with two different orientations, one for compound 1 and some of the conformers of SHU9119 and MTII, and the other for compound 2 and some other conformers of SHU9119 and MTII. The remaining conformers of SHU9119 and MTII, which did not map to compound 1 or 2, suggested that they were outside of the hMC-4R binding envelop. These observations may lead to conjectures as to why compound 1 is highly active and selective toward hMC-4R.

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Synthesis, Structure and Conformation of Partially‐Modified Retro‐ and Retro‐Inverso ψ[NHCH(CF₃)]Gly Peptides

Volonterio¹,

Bellosta²,

Bravin

et al. 2003

Chemistry A European J

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Partially modified retro- (PMR) and retro-inverso (PMRI) psi[NHCH(CF(3))]Gly peptides, a conceptually new class of peptidomimetics, have been synthesized in wide structural diversity and variable length by aza-Michael reaction of enantiomerically pure alpha-amino esters and peptides with enantiomerically and geometrically pure N-4,4,4-trifluorocrotonoyl-oxazolidin-2-ones. The factors underlying the observed moderate to good diastereocontrol have been investigated. The conformations of model PMR-psi[NHCH(CF(3))]Gly tripeptides have been studied in solution by (1)H NMR spectroscopy supported by MD calculations, as well as in the solid-state by X-ray diffraction. Remarkable stability of turn-like conformations, comparable to that of parent malonyl-based retropeptides, was evidenced, as a likely consequence of two main factors: 1) severe torsional restrictions about sp(3) bonds in the [CO-CH(2)-CH(CF(3))-NH-CH(R)-CO] module, which is biased by the stereoelectronically demanding CF(3) group and the R side chain; 2) formation of nine-membered intramolecularly hydrogen-bonded rings, which have been clearly detected both in CHCl(3) solution and in some crystal structures. The former factor seems to be more important, as turn-like conformations were found in the solid-state even in the absence of intramolecular hydrogen bonding. The relative configuration of the -C*H(CF(3))NHC*H(R)- stereogenic centers has a major effect on the stability of the turn-like conformation, which seems to require a syn stereochemistry. X-ray diffraction and ab initio computational studies showed that the [-CH(CF(3))NH-] group can be seen as a sort of hybrid between a peptide bond mimic and a proteolytic transition state analogue, as it combines some of the properties of a peptidyl -CONH- group (low NH basicity, CH(CF(3))-NH-CH backbone angle close to 120 degrees, C-CF(3) bond substantially isopolar with the C=O) with some others of the tetrahedral intermediate [-C(OX)(O(-))NH-] involved in the protease-mediated hydrolysis reaction of a peptide bond (high electron density on the CF(3) group, tetrahedral backbone carbon).

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Structure-function studies on the cyclic peptide MT-II, lactam derivative of α-melanotropin

Cited by 72 publications

References 31 publications

Analogs of α‐melanocyte stimulating hormone with high agonist potency and selectivity at human melanocortin receptor 1b: The role of Trp⁹ in molecular recognition

Analogs of α‐melanocyte stimulating hormone with high agonist potency and selectivity at human melanocortin receptor 1b: The role of Trp⁹ in molecular recognition

¹H‐NMR studies on a potent and selective antagonist at human melanocortin receptor 4 (hMC‐4R)

Synthesis, Structure and Conformation of Partially‐Modified Retro‐ and Retro‐Inverso ψ[NHCH(CF₃)]Gly Peptides

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Structure-function studies on the cyclic peptide MT-II, lactam derivative of α-melanotropin

Cited by 72 publications

References 31 publications

Analogs of α‐melanocyte stimulating hormone with high agonist potency and selectivity at human melanocortin receptor 1b: The role of Trp9 in molecular recognition

Analogs of α‐melanocyte stimulating hormone with high agonist potency and selectivity at human melanocortin receptor 1b: The role of Trp9 in molecular recognition

1H‐NMR studies on a potent and selective antagonist at human melanocortin receptor 4 (hMC‐4R)

Synthesis, Structure and Conformation of Partially‐Modified Retro‐ and Retro‐Inverso ψ[NHCH(CF3)]Gly Peptides

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Product

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Analogs of α‐melanocyte stimulating hormone with high agonist potency and selectivity at human melanocortin receptor 1b: The role of Trp⁹ in molecular recognition

Analogs of α‐melanocyte stimulating hormone with high agonist potency and selectivity at human melanocortin receptor 1b: The role of Trp⁹ in molecular recognition

¹H‐NMR studies on a potent and selective antagonist at human melanocortin receptor 4 (hMC‐4R)

Synthesis, Structure and Conformation of Partially‐Modified Retro‐ and Retro‐Inverso ψ[NHCH(CF₃)]Gly Peptides