Nucleic acid inhibitors of glutamate receptors
The present invention relates to novel nucleic acid ligands or aptamers that bind to and inhibit the activation of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of ionotropic glutamate receptors. Also disclosed is a novel combination of technologies, i.e., SELEX and laser pulse photolysis for the selection and screening of aptamers that inhibit receptor function and are useful therefore, in the treatment of diseases associated with excessive activation of ionotropic glutamate receptors.
1. An isolated nucleic acid comprising the nucleotide sequence of at least nucleotides 1-57 of SEQ ID NO: 5 and between 1 to 40 additional contiguous nucleotides corresponding to nucleotides 58 to 97 of SEQ ID NO: 5, wherein said isolated nucleic acid binds to a glutamate receptor.
2. The isolated nucleic acid of claim 1 , wherein said nucleic acid is RNA.
3. The isolated nucleic acid of claim 1 , wherein the nucleic acid contains between 58 and 150 nucleotides.
4. The isolated nucleic acid of claim 1 , wherein the nucleic acid contains between 58 and 100 nucleotides.
5. The isolated nucleic acid of claim 1 , wherein said nucleic acid contains one or more chemically modified nucleotides.
6. The isolated nucleic acid of claim 5 wherein the one or more chemically modified nucleotides has a 2′ fluoro substituent.
7. The isolated nucleic acid of claim 1 , wherein said nucleic acid inhibits glutamate receptor function.
8. The isolated nucleic acid of claim 1 wherein the glutamate receptor is of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) subtype.
9. An isolated DNA that codes for the RNA of claim 2 .
10. A method of inhibiting a glutamate receptor comprising contacting said receptor with the nucleic acid of claim 1 .
11. The method of claim 10 , wherein the glutamate receptor is of the AMPA subtype.