Conantokins

Abstract

The present invention is directed to conantokin peptides, conantokin peptide derivatives and conantokin peptide chimeras, referred to collectively as conantokins, having 10-30 amino acids, including preferably two or more γ-carboxyglutamic acid residues. The contantokins are useful for the treatment of neurologic and psychiatric disorders, such as anticonvulsant agents, neuroprotective agents or analgesic agents.

What is claimed is:  
     
         1 . An isolated nucleic acid sequence coding for a conantokin selected from the group consisting of Conantokin G (Con G) having the amino acid sequence Gly-Glu-Xaa 1 -Xaa 1 -Leu-Gin-Xaa 2 -Asn-Gln-Xaa 2 -Leu-Ile-Arg-Xaa 2 -Lys-Ser-Asn (SEQ ID NO: 1), Conantokin T (Con T) having the amino acid sequence Gly-Glu-Xaa 1 -Xaa 1 -Tyr-Gln-Lys-Met-Leu-Xaa 2 -Asn-Leu-Arg-Xaa 2 -Ala-Glu-Val-Lys-Lys-Asn-Ala (SEQ ID NO:2), Conatokin L (Con L) having the amino acid sequence Gly-Glu-Xaa 1 -Xaa 1 -Val-Ala-Lys-Met-Ala-Ala-Xaa 2 -Leu-Ala-Arg-Xaa 2 -Asp-Ala-Val-Asn (SEQ ID NO:3), Conantokin R (Con R) having the amino acid sequence Gly-Glu-Xaa 1 -Xaa 1 -Val-Ala-Lys-Met-Ala-Ala-Xaa 2 -Leu-Ala-Arg-Xaa 2 -Asn-Ile-Ala-Lys-Gly-Cys-Lys-Val-Asn-Cys-Tyr-Pro (SEQ ID NO:4), Conantokin S1 (Con S1) having the amino acid sequence Gly-Asp-Xaa 1 -Xaa 1 -Tyr-Ser-Lys-Phe-le-Xaa 2 -Arg-Glu-Arg-Xaa 2 -Ala-Gly-Arg-Leu-Asp-Leu-Ser-Lys-Phe-Pro (SEQ ID NO:5), Conantokin Oc (Con Oc) having the amino acid sequence Gly-Glu-Xaa 1 -Xaa 1 -Tyr-Arg-Lys-Ala-Met-Ala-Xaa 2 -Leu-Glu-Ala-Lys-Lys-Ala-Gln-Xaa 2 -Ala-Leu-Lys-Ala (SEQ ID NO:6), Conantokin Gm (Con Gm) having the amino acid sequence Gly-Ala-Lys-Xaa 1 -Asp-Arg-Asn-Asn-Ala-Xaa 2 -Ala-Val-Arg-Xaa 2 -Arg-Leu-Glu-Glu-Ile (SEQ ID NO:7), Conantokin Ca2 (Con Ca2) having the amino acid sequence Gly-Tyr-Xaa 1 -Xaa 1 -Asp-Arg-Xaa 2 -Ile-Ala-Xaa 2 -Thr-Val-Arg-Xaa 2 -Leu-Glu-Glu-Ala (SEQ ID NO:8), Conantokin Qu (Con Qu) having the amino acid sequence Gly-Tyr-Xaa 1 -Xaa 1 -Asp-Arg-Xaa 2 -Val-Ala-Xaa 2 -Thr-Val-Arg- having the amino acid sequence the formula: Gly-Asn-Asp-Val-Asp-Arg-Lys-Leu-Ala-Xaa 2 -Leu-Xaa 2 -Xaa 2 -Leu-Tyr-Xaa 2 -Ile (SEQ ID NO:68), wherein Xaa 1  γ-carboxyglutamic acid and Xaa 2  is selected from the group consisting of γ-carboxyglutamic acid, Ala, Ser, Glu, Tyr and phospo-Ser.  
     
     
         2 . The isolated nucleic acid of  claim 1 , wherein Xaa 2  is γ-carboxyglutamic acid.  
     
     
         3 . The isolated nucleic acid of  claim 2 , wherein said conantokin is selected from the group consisting of Con G, Con R, Con Oc, Con S1, Con L, Con Gm, Con Ca2 and Con Qu.  
     
     
         4 . The isolated nucleic acid sequence of  claim 3  selected from the group consisting of a DNA comprising the nucleotide sequence set forth in SEQ ID NO:45, a DNA comprising the nucleotide sequence set forth in SEQ ID NO:49, a DNA comprising the nucleotide sequence set forth in SEQ ID NO:53, a DNA comprising the nucleotide sequence set forth in SEQ ID NO:55, a DNA comprising the nucleotide sequence set forth in SEQ ID NO:57, a DNA comprising the nucleotide sequence set forth in SEQ ID NO:61, a DNA comprising the nucleotide sequence set forth in SEQ ID NO:63 and a DNA comprising the nucleotide sequence set forth in SEQ ID NO:65.  
     
     
         5 . A process for identifying nucleic acids encoding conantokins which comprises obtaining a sample containing Conus nucleic acid; subjecting said nucleic acid to amplification using primers selected from the group consisting of an oligonucleotide comprising the DNA sequence set forth in SEQ ID NO:44, an oligonucleotide comprising the DNA sequence set forth in SEQ ID NO:47, an oligonucleotide comprising the DNA sequence set forth in SEQ ID NO:48, an oligonucleotide comprising the DNA sequence set forth in SEQ ID NO:51, an oligonucleotide comprising the DNA sequence set forth in SEQ ID NO:59, and an oligonucleotide which is complimentary to a DNA sequence encoding the peptide comprising the amino acid sequence set forth in SEQ ID NO:67 to form amplification products; and identifying said amplification products.  
     
     
         6 . An oligonucleotide primer selected from the group consisting of oligonucleotide comprising the DNA sequence set forth in SEQ ID NO:44, an oligonucleotide comprising the DNA sequence set forth in SEQ ID NO:47, an oligonucleotide comprising the DNA sequence set forth in SEQ ID NO:48, an oligonucleotide comprising the DNA sequence set forth in SEQ ID NO:51, an oligonucleotide comprising the DNA sequence set forth in SEQ ID NO:59, and an oligonucleotide which is complimentary to a DNA sequence encoding the peptide comprising the amino acid sequence set forth in SEQ ID NO:67.