Cell-permeable and plasma-stable peptidomimetic inhibitors of the postsynaptic density-95/N-methyl-D-aspartate receptor interaction

Research output: Contribution to journalJournal articleResearchpeer-review

Standard

Cell-permeable and plasma-stable peptidomimetic inhibitors of the postsynaptic density-95/N-methyl-D-aspartate receptor interaction. / Bach, Anders*; Eildal, Jonas Nii Nortey*; Stuhr-Hansen, Nicolai; Deeskamp, Rasmus; Gottschalk, Marie; Pedersen, Søren Wittrup; Kristensen, Anders Skov; Strømgaard, Kristian (*Shared 1st authors).

In: Journal of Medicinal Chemistry, Vol. 54, No. 5, 10.03.2011, p. 1333-1346.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Bach, A, Eildal, JNN, Stuhr-Hansen, N, Deeskamp, R, Gottschalk, M, Pedersen, SW, Kristensen, AS & Strømgaard, KSA 2011, 'Cell-permeable and plasma-stable peptidomimetic inhibitors of the postsynaptic density-95/N-methyl-D-aspartate receptor interaction', Journal of Medicinal Chemistry, vol. 54, no. 5, pp. 1333-1346. https://doi.org/10.1021/jm1013924

APA

Bach, A., Eildal, J. N. N., Stuhr-Hansen, N., Deeskamp, R., Gottschalk, M., Pedersen, S. W., ... Strømgaard, K. S. . A. (2011). Cell-permeable and plasma-stable peptidomimetic inhibitors of the postsynaptic density-95/N-methyl-D-aspartate receptor interaction. Journal of Medicinal Chemistry, 54(5), 1333-1346. https://doi.org/10.1021/jm1013924

Vancouver

Bach A, Eildal JNN, Stuhr-Hansen N, Deeskamp R, Gottschalk M, Pedersen SW et al. Cell-permeable and plasma-stable peptidomimetic inhibitors of the postsynaptic density-95/N-methyl-D-aspartate receptor interaction. Journal of Medicinal Chemistry. 2011 Mar 10;54(5):1333-1346. https://doi.org/10.1021/jm1013924

Author

Bach, Anders* ; Eildal, Jonas Nii Nortey* ; Stuhr-Hansen, Nicolai ; Deeskamp, Rasmus ; Gottschalk, Marie ; Pedersen, Søren Wittrup ; Kristensen, Anders Skov ; Strømgaard, Kristian (*Shared 1st authors). / Cell-permeable and plasma-stable peptidomimetic inhibitors of the postsynaptic density-95/N-methyl-D-aspartate receptor interaction. In: Journal of Medicinal Chemistry. 2011 ; Vol. 54, No. 5. pp. 1333-1346.

Bibtex

@article{be91581598434de49615175809fde137,
title = "Cell-permeable and plasma-stable peptidomimetic inhibitors of the postsynaptic density-95/N-methyl-D-aspartate receptor interaction",
abstract = "The protein--protein interaction between the NMDA receptor and its intracellular scaffolding protein, PSD-95, is a potential target for treating ischemic brain diseases, neuropathic pain, and Alzheimer's disease. We have previously demonstrated that N-alkylated tetrapeptides are potent inhibitors of this interaction, and here, this template is exploited for the development of blood plasma-stable and cell-permeable inhibitors. Initially, we explored both the amino acid sequence of the tetrapeptide and the nature of the N-alkyl groups, which consolidated N-cyclohexylethyl-ETAV (1) as the most potent and selective compound. Next, the amide moieties of N-methylated ETAV were systematically replaced with thioamides, demonstrating that one of three amide bonds could be replaced without compromising the affinity. Subsequent optimization of the N-alkyl groups and evaluation of cell permeability led to identification of N-cyclohexylethyl-ETA(S)V (54) as the most potent, plasma-stable and cell-permeable inhibitor, which is a promising tool in unraveling the therapeutic potential of the PSD-95/NMDA receptor interaction.",
keywords = "Former Faculty of Pharmaceutical Sciences",
author = "Anders* Bach and Eildal, {Jonas Nii Nortey*} and Nicolai Stuhr-Hansen and Rasmus Deeskamp and Marie Gottschalk and Pedersen, {S{\o}ren Wittrup} and Kristensen, {Anders Skov} and Str{\o}mgaard, {Kristian (*Shared 1st authors)}",
year = "2011",
month = "3",
day = "10",
doi = "10.1021/jm1013924",
language = "English",
volume = "54",
pages = "1333--1346",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "5",

}

RIS

TY - JOUR

T1 - Cell-permeable and plasma-stable peptidomimetic inhibitors of the postsynaptic density-95/N-methyl-D-aspartate receptor interaction

AU - Bach, Anders

AU - Eildal, Jonas Nii Nortey

AU - Stuhr-Hansen, Nicolai

AU - Deeskamp, Rasmus

AU - Gottschalk, Marie

AU - Pedersen, Søren Wittrup

AU - Kristensen, Anders Skov

AU - Strømgaard, Kristian (Shared 1st authors)

PY - 2011/3/10

Y1 - 2011/3/10

N2 - The protein--protein interaction between the NMDA receptor and its intracellular scaffolding protein, PSD-95, is a potential target for treating ischemic brain diseases, neuropathic pain, and Alzheimer's disease. We have previously demonstrated that N-alkylated tetrapeptides are potent inhibitors of this interaction, and here, this template is exploited for the development of blood plasma-stable and cell-permeable inhibitors. Initially, we explored both the amino acid sequence of the tetrapeptide and the nature of the N-alkyl groups, which consolidated N-cyclohexylethyl-ETAV (1) as the most potent and selective compound. Next, the amide moieties of N-methylated ETAV were systematically replaced with thioamides, demonstrating that one of three amide bonds could be replaced without compromising the affinity. Subsequent optimization of the N-alkyl groups and evaluation of cell permeability led to identification of N-cyclohexylethyl-ETA(S)V (54) as the most potent, plasma-stable and cell-permeable inhibitor, which is a promising tool in unraveling the therapeutic potential of the PSD-95/NMDA receptor interaction.

AB - The protein--protein interaction between the NMDA receptor and its intracellular scaffolding protein, PSD-95, is a potential target for treating ischemic brain diseases, neuropathic pain, and Alzheimer's disease. We have previously demonstrated that N-alkylated tetrapeptides are potent inhibitors of this interaction, and here, this template is exploited for the development of blood plasma-stable and cell-permeable inhibitors. Initially, we explored both the amino acid sequence of the tetrapeptide and the nature of the N-alkyl groups, which consolidated N-cyclohexylethyl-ETAV (1) as the most potent and selective compound. Next, the amide moieties of N-methylated ETAV were systematically replaced with thioamides, demonstrating that one of three amide bonds could be replaced without compromising the affinity. Subsequent optimization of the N-alkyl groups and evaluation of cell permeability led to identification of N-cyclohexylethyl-ETA(S)V (54) as the most potent, plasma-stable and cell-permeable inhibitor, which is a promising tool in unraveling the therapeutic potential of the PSD-95/NMDA receptor interaction.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1021/jm1013924

DO - 10.1021/jm1013924

M3 - Journal article

C2 - 21322614

VL - 54

SP - 1333

EP - 1346

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 5

ER -

ID: 33239281