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

Research output: Contribution to journalJournal articlepeer-review

Standard

Modified peptides as potent inhibitors of the postsynaptic density-95/N-methyl-D-aspartate receptor interaction. / Bach, Anders; Chi, Celestine N.; Olsen, Thomas B.; Pedersen, Søren Wittrup; Røder, Martin U.; Pang, Gar Fai; Clausen, Rasmus Prætorius; Jemth, Per; Strømgaard, Kristian.

In: Journal of Medicinal Chemistry, Vol. 51, No. 20, 2008, p. 6450-6459.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Bach, A, Chi, CN, Olsen, TB, Pedersen, SW, Røder, MU, Pang, GF, Clausen, RP, Jemth, P & Strømgaard, K 2008, 'Modified peptides as potent inhibitors of the postsynaptic density-95/N-methyl-D-aspartate receptor interaction', Journal of Medicinal Chemistry, vol. 51, no. 20, pp. 6450-6459. https://doi.org/10.1021/jm800836w

APA

Bach, A., Chi, C. N., Olsen, T. B., Pedersen, S. W., Røder, M. U., Pang, G. F., Clausen, R. P., Jemth, P., & Strømgaard, K. (2008). Modified peptides as potent inhibitors of the postsynaptic density-95/N-methyl-D-aspartate receptor interaction. Journal of Medicinal Chemistry, 51(20), 6450-6459. https://doi.org/10.1021/jm800836w

Vancouver

Bach A, Chi CN, Olsen TB, Pedersen SW, Røder MU, Pang GF et al. Modified peptides as potent inhibitors of the postsynaptic density-95/N-methyl-D-aspartate receptor interaction. Journal of Medicinal Chemistry. 2008;51(20):6450-6459. https://doi.org/10.1021/jm800836w

Author

Bach, Anders ; Chi, Celestine N. ; Olsen, Thomas B. ; Pedersen, Søren Wittrup ; Røder, Martin U. ; Pang, Gar Fai ; Clausen, Rasmus Prætorius ; Jemth, Per ; Strømgaard, Kristian. / Modified peptides as potent inhibitors of the postsynaptic density-95/N-methyl-D-aspartate receptor interaction. In: Journal of Medicinal Chemistry. 2008 ; Vol. 51, No. 20. pp. 6450-6459.

Bibtex

@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",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "20",

}

RIS

TY - JOUR

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

VL - 51

SP - 6450

EP - 6459

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 20

ER -

ID: 8378399