Konformation und biologische Wirkung von cyclischen Peptiden

Kessler, Horst

doi:10.1002/ange.19820940705

Cited by 246 publications

(18 citation statements)

References 145 publications

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“…[17] In principle, it is possible to improve the efficacy of such a flexible molecule by modifying its geometry, [5a] taking into consideration that "the more the structure of a free ligand in solution resembles the structure in the complex, the stronger the binding". [18] Despite the many limitations, this assumption sometimes works very well as an indicative guide for structure optimization. Consequently, we supposed that analogues of 4 having the inverse type II b-turn on d-Trp-Phe might show improved receptor affinity, therefore confirming that this secondary structure represents the bioactive conformation.…”

Section: Cyclopeptide Designmentioning

confidence: 99%

The Inverse Type II β‐Turn on D‐Trp‐Phe, a Pharmacophoric Motif for MOR Agonists

et al. 2011

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Herein we propose the D-Trp-Phe sequence within an inverse type II β-turn as a new kind of pharmacophoric motif for μ-opioid receptor (MOR) cyclopeptide agonists. Initially, we observed that c[Tyr-D-Pro-D-Trp-Phe-Gly] (4), an analogue of endomorphin-1 (H-Tyr-Pro-Trp-Phe-NH₂) lacking the crucial protonatable amino group of Tyr 1, is a MOR agonist with 10⁻⁸ M affinity. Molecular docking analysis suggested that the relevant interactions with the receptor involve D-Trp-Phe. The bioactive conformation of this region was investigated by selected derivatives of 4 designed to adopt an inverse type II β-turn. These efforts led to c[Tyr-Gly-D-Trp-Phe-Gly] (14) and to the cyclotetrapeptide c[D-Asp-1-amide-β-Ala-D-Trp-Phe] (15), showing improved nanomolar affinity. Both 14 and 15 selectively bind MOR, as they have negligible affinity for the κ- and δ-opioid receptors. Both 14 and 15 behave as partial MOR agonists in functional assays. Conformational and docking analyses confirm the role of the inverse β-turn in binding. These results indicate that the D-Trp-Phe inverse β-turn structure can be used for designing non-endomorphin-like peptidomimetic opioid agonists in general, characterized by an atypical mechanism of interaction between ligand and receptor.

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Section: Cyclopeptide Designmentioning

confidence: 99%

The Inverse Type II β‐Turn on D‐Trp‐Phe, a Pharmacophoric Motif for MOR Agonists

et al. 2011

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“…[25] All other amide protons, on the other hand, appear to be solvent-exposed. Note that for the completely solvent-exposed amide and thioamide protons of NMA and NMTAA (N-methylthioacetamide; the thio-substituted analogue of NMA) we measured values of À6.9 10 À3 and À3.8·10 À3 ppm K…”

mentioning

confidence: 98%

Coexistence of Hydrogen‐Bonded Loop and Extended Tetrapeptide Conformations

Cervetto

Pfister

Kolano

et al. 2007

Chemistry A European J

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The conformations of a protected tetrathiopeptide have been analysed by isotope labelling and two-dimensional infrared spectroscopy (2D-IR). It has been found that Boc-Ala-Gly(=S)-Ala-Aib-OMe in acetonitrile, as well as its oxopeptide analogue, can adopt a hydrogen-bonded loop conformation in coexistence with less restricted structures. The two types of conformations interconvert too quickly to be resolved on the nuclear magnetic resonance (NMR) timescale, but give rise to different cross peaks in two-dimensional infrared spectra. The hydrogen bond between the Boc terminal group and the amide proton of Aib can be broken by photoisomerisation of the thioamide bond.

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“…Such studies will lead to a new blossoming of organic chemistry in the future." [1] This still holds true. However, we now realize that extremely complicated multidimensional networks of interactions of a vast number of biomolecules determine biological chemistry and regulatory pathways.…”

mentioning

confidence: 62%