Molecular interactions in neurons
AssigneeArbor Vita Corporation
InventorsPeter Lu, Jonathan Garman, Michael Belmares
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Abstract
Inhibitors that disrupt binding between a PDZ protein and cognate ligands such as N-methyl-D-aspartate (NMDA) receptors that are involved in various neurological disorders are provided. Pharmaceutical compositions containing such inhibitors and their use in treating neurological diseases such as stroke and ischemia are also disclosed. Screening methods to identify additional inhibitors of specific protein ligand interactions with PDZ proteins are also described.
Claims74
An inhibitor comprising an isolated, recombinant or synthetic polypeptide that inhibits binding between a N-methyl-D-aspartate (NMDA) receptor and a PDZ protein.
A method for inhibiting binding between a N-methyl-D-aspartate (NMDA) receptor and a PDZ protein in a neuron cell, comprising introducing into the cell a polypeptide that inhibits binding between the NMDA receptor and a PDZ protein and comprises a C-terminal amino acid sequence of X-T-X-V/L/A.
A method for inhibiting binding between a N-methyl-D-aspartate (NMDA) receptor and a PDZ protein in a neuron cell, comprising introducing into the cell a polypeptide that inhibits binding of the NMDA receptor and a PDZ protein, wherein the PDZ protein is selected from the group consisting of DLG1, DLG2, KIAA0973, NeDLG, Outermembrane protein, Syntrophin alpha 1, TIP1, TIP2, INADL, KIAA0807, KIAA1634, Lim-Mystique, LIM-RIL, MAGI1, MAGI2, Syntrophin beta-1 and Syntrophin gamma-1.
A method for inhibiting binding between a N-methyl-D-aspartate (NMDA) receptor and a PDZ protein in a neuron cell, comprising introducing into the cell a polypeptide that inhibits binding of the NMDA receptor and a PDZ protein and is 3 amino acids in length.
A method for determining whether a test compound inhibits binding between a PDZ protein and a N-methyl-D-aspartate (NMDA) receptor, comprising:
- (a) contacting a PDZ-domain polypeptide comprising a PDZ domain from the PDZ protein and a PL peptide that comprises at least the C-terminal 3 amino acids of the NMDA receptor in the presence of the test compound, wherein the PDZ protein is selected from the group listed in TABLE 7;
- (b) determining the concentration of complex formed between the PDZ-domain polypeptide and the PL peptide;
- and
- (c) identifying the test compound as a potential inhibitor of binding between the PDZ protein and the NMDA receptor if a lower concentration of the complex is detected in the presence of the test compound relative to the concentration of the complex in the absence of the test compound.
A pharmaceutical composition comprising a polypeptide that inhibits binding between a N-methyl-D-aspartate (NMDA) receptor and a PDZ protein and a physiologically acceptable carrier, diluent or excipient, wherein the polypeptide is a fusion of (i) a 9 amino acid segment whose C-terminal sequence is selected from the group of amino acid sequences consisting of ETEV, ETQL, QTQV, ETAL, QTEV, ETVA and FTDV and (ii) an amino acid segment of a transmembrane transporter that is effective to transport the polypeptide into a neuron.
A method for inhibiting binding between a N-methyl-D-aspartate (NMDA) receptor and a PDZ protein in a neuron cell, comprising introducing into the cell a polypeptide that inhibits binding between the NMDA receptor and the PDZ protein, wherein the polypeptide is a fusion of (i) a 9 amino acid segment whose C-terminal sequence is selected from the group of amino acid sequences consisting of ETEV, ETQL, QTQV, ETAL, QTEV, ETVA and FTDV and (ii) an amino acid segment of a transmembrane transporter that is effective to transport the polypeptide into a neuron.
Dependencies are inferred from the claim text.