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

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Former Faculty of Pharmaceutical Sciences

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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

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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.",

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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)

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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.

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ER -

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

Abstract

Keywords

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