Pyrroloisoquinoline-Based Tetrapeptide Analogues Mimicking Reverse-Turn Secondary Structures
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Abstract:
New pyrroloisoquinoline-based tetrapeptides were synthesized in enantiomerically pure form, and their conformational features were studied by NMR, IR, and molecular-modeling techniques. The presence of a reverse turn was observed in both structures, with the C1 stereochemistry playing a central role in determining stable conformations. In particular, all of the analyses led to the conclusion that a type II' beta-turn is mostly stabilized in tetrapeptide mimic 3a, while a typical inverse gamma-turn geometry is revealed for the diastereoisomer 3b.Keywords:
Tetrapeptide
Turn (biochemistry)
Diastereomer
Molecular model
Abstract N-Acetyl-l-Leu–X–l-Pro–l-Val methylamides (IIa: X=d-Ala, IIb: X=Gly, IIc: X=l-Ala) were synthesized and subjected to CD and 1H NMR measurements to study the β-turn preferences of these peptides. Temperature dependences of l-Val4–NH proton chemical shifts in CD3OH solution were in the order of IIa<IIb<IIc, suggesting that the populations of the β-turn conformer with 4→1 hydrogen bonding were in the order of IIa>IIb>IIc. This order of β-turn preferences coincides with the order of the magnitudes of the Cotton effects in the CD spectra of the chromophoric derivatives, N-(2,4-dinitrophenyl)tetrapeptide p-nitroanilides, having the same sequences. This agreement supports the validity of the chiroptical method to study turn tendency of tetrapeptide sequences using chromophoric derivatives reported previously.
Turn (biochemistry)
Tetrapeptide
Gramicidin S
Conformational isomerism
Turn-Taking
Proton NMR
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The dermorphin-derived cyclic tetrapeptide analogues H-Tyr-c[D-Cys-Phe-Cys]NH(2) and H-Tyr-c[D-Cys-Phe-D-Cys]NH(2) are opioid agonists at the mu and delta receptor. To enhance the metabolic stability of these peptides, we replaced the disulfide bridge with a bis-methylene moiety. This was achieved by solid-phase synthesis of the linear precursor peptide containing allylglycine residues in place of the Cys residues, followed by ring-closing metathesis. In the case of the peptide with L-configuration in the 4-position both the cis and the trans isomer of the resulting olefinic peptides were formed, whereas the cis isomer only was obtained with the peptide having the D-configuration in position 4. Catalytic hydrogenation yielded the saturated -CH(2)-CH(2)- bridged peptides. In comparison with the cystine-containing parent peptides, all olefinic peptides showed significantly reduced mu and delta agonist potencies in the guinea pig ileum and mouse vas deferens assays. The -CH(2)-CH(2)-bridged peptide with l-configuration in the 4-position was equipotent with its cystine-containing parent in both assays, whereas the bis-methylene analogue with D-configuration in position 4 was 10-27-fold less potent compared to its parent. The effect of the disulfide replacements with the -CH=CH- and -CH(2)-CH(2)- moieties on the conformational behavior of these peptides was examined by theoretical conformational analysis which provided plausible explanations in terms of structural parameters for the observed changes in opioid activity.
Dermorphin
Tetrapeptide
Tripeptide
Peptide Synthesis
Ring-Closing Metathesis
Moiety
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The effect of changing 1st and 4th amino acid residues on beta-turn preference of tetrapeptide sequences was studied by use of CD spectra of th chromophoric derivatives, which have Dnp- and pNA-groups as the amino and carboxyl substituents, respectively. The effect was examined with the tetrapeptides having such sequences at the 2nd and 3rd positions as -L-Pro-L-Asn-, -L-Pro-Gly-, -L-Pro-D-Ala-, -L-Ala-D-Leu-, -L-Ala-L-Pro-, and -D-Ala-L-Pro-. The beta-turn preferences estimated from the CD intensities of the bands due to exciton interaction were found to depend largely on the configurations of the 1st and 4th amino acid residues. When 1st and 2nd (or 3rd and 4th) residues had the same configuration, decreased intensity of the CD band was observed even if the internal sequence had high beta-turn preference. Terminal Gly residues were favorable for the beta-turn conformation in many of the tetrapeptide sequences examined.
Tetrapeptide
Turn (biochemistry)
Amino terminal
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Abstract N-(2,4-Dinitrophenyl)tetrapeptide p-nitroanilides related to the β-turn part of gramicidin S were synthesized and subjected to CD measurements. The β-turn preference of the tetrapeptide derivatives had correlation with the antibiotic activities of the gramicidin S analogs containing similar tetrapeptide sequences at their β-turn part. So, conformational preference of partial sequences of gramicidin S analogs seem to play a significant role for determining their biological activities.
Tetrapeptide
Turn (biochemistry)
Gramicidin S
Dinitrophenyl
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Tetrapeptide
Cyclic peptide
Absolute Configuration
Residue (chemistry)
Side chain
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We report the synthesis, biological activity, and conformational analysis of tetrapeptide analogs related to [Val4]morphiceptin and [D-Val4]morphiceptin in which the proline at the second position has been replaced with cis-2-aminocyclopentane carboxylic acid (cis-2-Ac5c). Since the cis-2-Ac5c residue contains a normal amide, only the trans form has been observed about the amide bond between the first and second residues. The cis-2-Ac5c is a beta amino acid with two chiral centers resulting in two possible configurational isomers, namely (1S, 2R) and 1R, 2S) forms. The analogs containing the (1S, 2R)-Ac5c residue show activity at the mu-receptor but are inactive at the delta-receptor, resulting in a high selectivity for the mu-receptor. The (1R,2S)-Ac5c containing analogs are completely inactive at both the mu- and delta-receptors. The conformational analysis indicates that the separation of the aromatic rings of the tyrosine and phenylalanine residues, as expressed by the center-to-center distance, is 10.1-12.7 A for the preferred conformations of the bioactive analogs containing the (1S,2R)-Ac5c residue while a range of 4.8-7.0 A is observed for the preferred conformations of the inactive analogs with the (IR,2S)-Ac5c residue. A comparison of the findings from the conformational analysis and biological assays establishes the fact that a relatively large separation of the two aromatic side chains is required for the mu-opioid receptor activity of these molecules. Since the tetrapeptide amides studied in this investigation show similar biological profiles to those of the morphiceptin-related analogs, we have compared the preferred conformations estimated for the cis-2-Ac5c containing analogs with those of morphiceptin. One of the low energy conformations calculated for morphiceptin with the cis form about the tyrosine and proline residues has considerable topological similarity with the bioactive analogs containing the (1S,2R)-Ac5c residue, indicating that the cis from about these two residues is required for the biological activity of the morphiceptin-related analogs containing the proline at the second position.
Tetrapeptide
Residue (chemistry)
Dermorphin
Amide
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Abstract To confirm the general applicability of CD spectra of N-(2,4-dinitrophenyl(Dnp))tetrapeptide p-nitroanilides (pNA’s) to the analysis of β-turn preference of the tetrapeptide sequences, Dnp-pNA derivatives of some tetrapeptides related to β-turn preferring sequences in proteins were synthesized and subjected to CD and 1H NMR measurements. CD spectra of Dnp–Gly–l-Pro–l-Asn–Gly–pNA (5a) were just the mirror image of those of gramicidin S-model peptide, Dnp–Gly–d-Ala–l-Pro–Gly–pNA (6). This suggested that 5a strongly preferred the β-turn and the type of turn was different from that of 6. The relative intensities of Cotton effects of the tetrapeptide with the general structure Dnp–Gly–l-Pro–Y–Gly–pNA (Y=l-Asn, Gly, l-Ala, or l-Gln) roughly agreed with the bend potentials of the amino acid residues at the third position of β-turns in proteins reported by Chou and Fasman. The effects of changing the amino acid residues at the second position of β-turn were also examined.
Tetrapeptide
Turn (biochemistry)
Dinitrophenyl
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Frangulanine is a peptide alkaloid, with a 14 membered macrocyclic ring, from Hovenia dulcis THUNB. The X-ray analysis of frangulanine derivative and the synthetic study revealed the conformation of frangulanine as shown in Fig. 1 and Fig. 2. The tetrapeptide, Ile-Hyleu-Leu-Tyr, a hypothetical intermediate of frangulanine biosynthesis, was also synthesized.
Tetrapeptide
Derivative (finance)
Cyclic peptide
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Tetrapeptide
Turn (biochemistry)
BETA (programming language)
Sequence (biology)
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Citations (75)
Tetrapeptide
Dermorphin
Turn (biochemistry)
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Citations (15)