Are β-Amino Acids γ-Turn Mimetics? Exploring A New Design Principle for Bioactive Cyclopeptides

Schumann, F. O.; Müller, A.; Koksch, Mario; Müller, Gerhard; Sewald, Norbert

doi:10.1021/ja0016001

Cited by 98 publications

(79 citation statements)

References 12 publications

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“…Indeed, 4 contains two β-amino acid residues, Asp and Dap, and it has been demonstrated that the presence of β-residues in cyclotetrapeptides and cyclopentapeptides tends to favor the formation of the well-defined γ-or β-turn structures in opposite regions of the cyclic structure. [32][33][34] As for cyclopeptide 5, which has the same sequence as 1 deprived of one Phe residue, the analysis of the trajectories of MD showed a strong tendency to give a β-turn centered on Phe-Asp, with an H-bond between the CvO of D-Lys and D-LysNHε (Fig. 2).…”

Section: Correlation Between Ring Size and Receptor Affinity/selectivitymentioning

confidence: 89%

Ring size in cyclic endomorphin-2 analogs modulates receptor binding affinity and selectivity

et al. 2015

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The study reports the solid-phase synthesis and biological evaluation of a series of new side chain-toside chain cyclized opioid peptide analogs of the general structure Tyr-[D-Xaa-Phe-Phe-Asp]NH 2 , where Xaa = Lys (1), Orn (2), Dab (3), or Dap (4) (Dab = 2,4-diaminobutyric acid, Dap = 2,3-diaminopropionic acid), containing 17-to 14-membered rings. The influence of the ring size on binding to the MOP, DOP and KOP opioid receptors was studied. In general, the reduction of the size of the macrocyclic ring

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Section: Correlation Between Ring Size and Receptor Affinity/selectivitymentioning

confidence: 89%

Ring size in cyclic endomorphin-2 analogs modulates receptor binding affinity and selectivity

et al. 2015

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“…± The discovery of Seebach and Gellman and co-workers that bpeptides readily form various secondary structures, e.g., 14-helix, 12-helix, 10/12-helix, 10-helix, 2 8 -ribbon, turns, and pleated-sheets [1 ± 6], has generated tremendous excitement [7]. Since b-amino acids usually possess two stereogenic centers, a large number of structural variations are possible, which makes them interesting building blocks in molecular design [8]. According to circular dichroism (CD) spectra, some bpeptides appear to possess unknown secondary structures that still need to be solved [9].…”

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confidence: 99%

Theoretical Study of -Peptide Models: Intrinsic Preferences of Helical Structures

Lin

Zhao

2002

HCA

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Dedicated to Professor Dieter Seebach on the occasion of his 65th birthday b-Peptides form various secondary structures, such as 14-helix, 12-helix, 10/12-helix, 10-helix, 2 8 -ribbon, C6-ribbon, and pleated-sheet. Thus, it is useful to understand the intrinsic backbone conformational preferences of these basic structures. By using a simple repeating-unit method, we have calculated the preferences of C6-ribbon, b-strand, 10/12-helix, 14-helix, 12-helix, 10-helix, and 2 8 -ribbon of a series of poly-b-alanine models, Ac-(b-Ala) n -NH 2 , with n 1 ± 9. Interactions among single amino acids result in cooperative residue energies. This is not found for the formations of b-strands, 2 8 -ribbons, and C6-ribbons, which possess constant residue energies. In contrast, the 12-helix, 10-helix, and 14-helix are characterized by increasing residue energies as the peptide elongates. Therefore, there is a considerable positive cooperative impetus in the gas phase for their formation. The residue energy of the 10/12-helix increases significantly for n 2 and 3, and then displays a zigzag pattern. Meanwhile, there is a good correlation between calculated residue energies and residue dipole moments, indicating the importance of long-range electrostatic interactions to the cooperative residue energy. Efforts have been made to separate the electrostatic and torsional interactions between residues. Thereby, the 12-, 10-, and 10/12-helices all benefit from electrostatic interactions, while the 14-helix has the most intrinsic preference in terms of torsional interaction. The effect of MeOH on the secondary structures has also been evaluated by SCIPCM solvent model calculations.

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“…A recognition epitope, for example, the RGD sequence, is combined with a secondary-structure-inducing element, for example, a d-amino acid, [4] an N-alkyl-amino acid, [5] or a b-amino acid. [6] The cyclic pentapeptide cyclo-(-Arg-Gly-Asp-d-Phe-Val-) 1 was developed by Kessler and co-workers in a spatial screening approach as a very active and selective ligand of integrin a V b 3 . [7,8] Replacement of Val by its N-methyl derivative led to the cyclo-(-Arg-Gly-Asp-d-Phe-N(Me)-Val-) peptide with enhanced biological activity and selectivity to the integrin a V b 3 .…”

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confidence: 99%

“…If a single bamino acid is incorporated into a cyclic pentapeptide, it preferably occupies the central position of a g turn that is extended by one CH 2 group and hence called a pseudo-g turn (Yg). [6] The conformational bias of the b-amino acid may even exceed that of a d-amino acid residue. Thus, b-amino acids act as g-turn mimetics.…”

mentioning

confidence: 99%

“…Thus, b-amino acids act as g-turn mimetics. [6] cis-b-Aminocyclopropanecarboxylic acid (b-Acc) derivatives [12][13][14][15] have improved the stabilization of the secondary structure of peptides [16] and have been used for the synthesis of neuropeptide Y analogues with a higher affinity for the receptor subtype Y 1 . [17] b-Acc may be regarded as a chimera displaying structural features of a b-amino acid, with respect to conformational bias, and methyl aspartate, with respect to hydrogen-bond-acceptor capability.…”

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confidence: 99%

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The Constrained Amino Acid β‐Acc Confers Potency and Selectivity to Integrin Ligands

Urman¹,

Gaus²,

Yang³

et al. 2007

Angew Chem Int Ed

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Interactions between the extracellular matrix and membrane proteins are of importance for cell adhesion, tissue formation, and transmembrane signaling processes. Among cell adhesion molecules, integrins occupy a highly prominent position. Many integrins, among them a 5 b 1 and a V b 3 , recognize the tripeptide sequence -Arg-Gly-Asp-(RGD) in their ligands. The discovery of the role of the RGD sequence in cell-cell and cell-matrix interactions prompted the development of a broad variety of RGD peptides and peptidomimetics for potential therapeutic applications. Soluble derivatives of these compounds are able to competitively inhibit the interaction between an RGD-containing protein and its integrin counterpart, whereas immobilized RGD peptides support cell attachment, for example, to artificial implants.

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Are β-Amino Acids γ-Turn Mimetics? Exploring A New Design Principle for Bioactive Cyclopeptides

Cited by 98 publications

References 12 publications

Ring size in cyclic endomorphin-2 analogs modulates receptor binding affinity and selectivity

Ring size in cyclic endomorphin-2 analogs modulates receptor binding affinity and selectivity

Theoretical Study of -Peptide Models: Intrinsic Preferences of Helical Structures

The Constrained Amino Acid β‐Acc Confers Potency and Selectivity to Integrin Ligands

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