Modified peptides as potent inhibitors of the postsynaptic density-95/N-methyl-D-aspartate receptor interaction

Anders Bach; Celestine N. Chi; Thomas B. Olsen; Søren Wittrup Pedersen; Martin U. Røder; Gar Fai Pang; Rasmus Prætorius Clausen; Per Jemth; Kristian Strømgaard

doi:10.1021/jm800836w

Modified peptides as potent inhibitors of the postsynaptic density-95/N-methyl-D-aspartate receptor interaction

Anders Bach, Celestine N. Chi, Thomas B. Olsen, Søren Wittrup Pedersen, Martin U. Røder, Gar Fai Pang, Rasmus Prætorius Clausen, Per Jemth, Kristian Strømgaard

52 Citations (Scopus)

Abstract

The protein-protein interaction between the NMDA receptor and its intracellular scaffolding protein, PSD-95, is a potential target for treatment of ischemic brain diseases. An undecapeptide corresponding to the C-terminal of the NMDA was used as a template for finding lead candidates for the inhibition of the PSD-95/NMDA receptor interaction. Initially, truncation and alanine scan studies were carried out, which resulted in a pentapeptide with wild-type affinity, as examined in a fluorescence polarization assay. Further examination was performed by systematic substitutions with natural and unnatural amino acids, which disclosed a tripeptide with micromolar affinity and N-methylated tetrapeptides with improved affinities. Molecular modeling studies guided further N-terminal modifications and introduction of a range of N-terminal substitutions dramatically improved affinity. The best compound, N-cyclohexylethyl-ETAV (56), demonstrated up to 19-fold lower K i value ( K i = 0.94 and 0.45 microM against PDZ1 and PDZ2 of PSD-95, respectively) compared to wild-type values, providing the most potent inhibitors of this interaction reported so far. These novel and potent inhibitors provide an important basis for development of small molecule inhibitors of the PSD-95/NMDA receptor interaction.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	51
Issue number	20
Pages (from-to)	6450-6459
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm800836w
Publication status	Published - 2008

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Former Faculty of Pharmaceutical Sciences

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10.1021/jm800836w

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@article{73c357b0a9a611ddb5e9000ea68e967b,

title = "Modified peptides as potent 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 treatment of ischemic brain diseases. An undecapeptide corresponding to the C-terminal of the NMDA was used as a template for finding lead candidates for the inhibition of the PSD-95/NMDA receptor interaction. Initially, truncation and alanine scan studies were carried out, which resulted in a pentapeptide with wild-type affinity, as examined in a fluorescence polarization assay. Further examination was performed by systematic substitutions with natural and unnatural amino acids, which disclosed a tripeptide with micromolar affinity and N-methylated tetrapeptides with improved affinities. Molecular modeling studies guided further N-terminal modifications and introduction of a range of N-terminal substitutions dramatically improved affinity. The best compound, N-cyclohexylethyl-ETAV (56), demonstrated up to 19-fold lower K i value ( K i = 0.94 and 0.45 microM against PDZ1 and PDZ2 of PSD-95, respectively) compared to wild-type values, providing the most potent inhibitors of this interaction reported so far. These novel and potent inhibitors provide an important basis for development of small molecule inhibitors of the PSD-95/NMDA receptor interaction.",

keywords = "Former Faculty of Pharmaceutical Sciences",

author = "Anders Bach and Chi, {Celestine N.} and Olsen, {Thomas B.} and Pedersen, {S{\o}ren Wittrup} and R{\o}der, {Martin U.} and Pang, {Gar Fai} and Clausen, {Rasmus Pr{\ae}torius} and Per Jemth and Kristian Str{\o}mgaard",

year = "2008",

doi = "10.1021/jm800836w",

language = "English",

volume = "51",

pages = "6450--6459",

journal = "Journal of Medicinal Chemistry",

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T1 - Modified peptides as potent inhibitors of the postsynaptic density-95/N-methyl-D-aspartate receptor interaction

AU - Bach, Anders

AU - Chi, Celestine N.

AU - Olsen, Thomas B.

AU - Pedersen, Søren Wittrup

AU - Røder, Martin U.

AU - Pang, Gar Fai

AU - Clausen, Rasmus Prætorius

AU - Jemth, Per

AU - Strømgaard, Kristian

PY - 2008

Y1 - 2008

N2 - The protein-protein interaction between the NMDA receptor and its intracellular scaffolding protein, PSD-95, is a potential target for treatment of ischemic brain diseases. An undecapeptide corresponding to the C-terminal of the NMDA was used as a template for finding lead candidates for the inhibition of the PSD-95/NMDA receptor interaction. Initially, truncation and alanine scan studies were carried out, which resulted in a pentapeptide with wild-type affinity, as examined in a fluorescence polarization assay. Further examination was performed by systematic substitutions with natural and unnatural amino acids, which disclosed a tripeptide with micromolar affinity and N-methylated tetrapeptides with improved affinities. Molecular modeling studies guided further N-terminal modifications and introduction of a range of N-terminal substitutions dramatically improved affinity. The best compound, N-cyclohexylethyl-ETAV (56), demonstrated up to 19-fold lower K i value ( K i = 0.94 and 0.45 microM against PDZ1 and PDZ2 of PSD-95, respectively) compared to wild-type values, providing the most potent inhibitors of this interaction reported so far. These novel and potent inhibitors provide an important basis for development of small molecule inhibitors 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 treatment of ischemic brain diseases. An undecapeptide corresponding to the C-terminal of the NMDA was used as a template for finding lead candidates for the inhibition of the PSD-95/NMDA receptor interaction. Initially, truncation and alanine scan studies were carried out, which resulted in a pentapeptide with wild-type affinity, as examined in a fluorescence polarization assay. Further examination was performed by systematic substitutions with natural and unnatural amino acids, which disclosed a tripeptide with micromolar affinity and N-methylated tetrapeptides with improved affinities. Molecular modeling studies guided further N-terminal modifications and introduction of a range of N-terminal substitutions dramatically improved affinity. The best compound, N-cyclohexylethyl-ETAV (56), demonstrated up to 19-fold lower K i value ( K i = 0.94 and 0.45 microM against PDZ1 and PDZ2 of PSD-95, respectively) compared to wild-type values, providing the most potent inhibitors of this interaction reported so far. These novel and potent inhibitors provide an important basis for development of small molecule inhibitors of the PSD-95/NMDA receptor interaction.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1021/jm800836w

DO - 10.1021/jm800836w

M3 - Journal article

C2 - 18811137

SN - 0022-2623

VL - 51

SP - 6450

EP - 6459

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 20

ER -

Modified peptides as potent inhibitors of the postsynaptic density-95/N-methyl-D-aspartate receptor interaction

Abstract

Keywords

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