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

Anders* Bach; Jonas Nii Nortey* Eildal; Nicolai Stuhr-Hansen; Rasmus Deeskamp; Marie Gottschalk; Søren Wittrup Pedersen; Anders Skov Kristensen; Kristian (*Shared 1st authors) Strømgaard

doi:10.1021/jm1013924

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

Anders* Bach, Jonas Nii Nortey* Eildal, Nicolai Stuhr-Hansen, Rasmus Deeskamp, Marie Gottschalk, Søren Wittrup Pedersen, Anders Skov Kristensen, Kristian (*Shared 1st authors) Strømgaard

58 Citations (Scopus)

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.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	54
Issue number	5
Pages (from-to)	1333-1346
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm1013924
Publication status	Published - 10 Mar 2011

Keywords

Former Faculty of Pharmaceutical Sciences

Access to Document

10.1021/jm1013924

Cite this

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 et al.

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

Research output: Contribution to journal › Journal article › Research › peer-review

@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 = mar,

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",

}

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

SN - 0022-2623

VL - 54

SP - 1333

EP - 1346

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 5

ER -

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

Abstract

Keywords

Access to Document

Fingerprint

Cite this