Modified peptides as potent inhibitors of the postsynaptic density-95/N-methyl-D-aspartate receptor interaction
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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.
I: Journal of Medicinal Chemistry, Bind 51, Nr. 20, 2008, s. 6450-6459.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Harvard
APA
Vancouver
Author
Bibtex
}
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