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.
authors.affiliation: Department of Medicinal Chemistry, The Faculty of Pharmaceutical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Bach
authors.forename: Celestine N
authors.initials: CN
authors.lastname: Chi
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Olsen
authors.forename: Søren W
authors.initials: SW
authors.lastname: Pedersen
authors.forename: Martin U
authors.initials: MU
authors.lastname: Røder
authors.forename: Gar F
authors.initials: GF
authors.lastname: Pang
authors.forename: Rasmus P
authors.initials: RP
authors.lastname: Clausen
authors.forename: Per
authors.initials: P
authors.lastname: Jemth
authors.forename: Kristian
authors.initials: K
authors.lastname: Strømgaard
mesh_terms: D000107:Acetylation; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D017459:Receptors, Amino Acid / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D010455:Peptides; D017459:Receptors, Amino Acid; C031959:aspartic acid receptor