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

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

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 languageEnglish
JournalJournal of Medicinal Chemistry
Volume51
Issue number20
Pages (from-to)6450-6459
ISSN0022-2623
DOIs
Publication statusPublished - 2008

ID: 8378399