Isozyme-specific antagonists of protein kinase C
View Patent ↗A method of changing or otherwise converting the biological activity of a PKC peptide agonist to a peptide antagonist is described. The method involves substituting one or more amino acid residues so as to effect a change in charge in the peptide and/or to otherwise make the sequence similar to a sequence derived from the PKC binding site on the RACK protein for the respective PKC enzyme. Methods of inhibiting the activity of a PKC enzyme, and various peptide antagonists of εPKC are also disclosed.
1. A method of treating pain, comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising a first peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, and SEQ ID NO:57, wherein said first peptide is crosslinked via a Cys-Cys bond to a second peptide to facilitate cellular uptake.
2. The method of claim 1 , wherein said second peptide is selected from the group consisting of a Tat-derived peptide, an Antennapedia homeodomain-derived sequence, and a polyarginine peptide.
3. The method of claim 2 , wherein said second peptide is a the Tat-derived peptide and wherein the Tat-derived peptide comprises SEQ ID NO:92.
4. The method of claim 2 , wherein said second peptide is an Antennapedia homeodomain-derived sequence and the Antennapedia homeodomain-derived sequence comprises SEQ ID NO:91.
5. The method of claim 1 , wherein said administering is by a route selected from the group consisting of intravenous, parenteral, and subcutaneous.
6. The method of claim 1 , wherein said first peptide is crosslinked to said second peptide via an N-terminal Cys-Cys bond.
7. The method of claim 1 , wherein said first peptide comprises SEQ ID NO:50.
8. The method of claim 1 , wherein said first peptide comprises SEQ ID NO:51.
9. The method of claim 1 , wherein said first peptide comprises SEQ ID NO:52.
10. The method of claim 1 , wherein said first peptide comprises SEQ ID NO:53.
11. The method of claim 1 , wherein said first peptide comprises SEQ ID NO:54.
12. The method of claim 1 , wherein said first peptide comprises SEQ ID NO:55.
13. The method of claim 1 , wherein said first peptide comprises SEQ ID NO:56.
14. The method of claim 1 , wherein said first peptide comprises SEQ ID NO:57.
15. A method of treating pain, comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising a first peptide comprising the amino acid sequence of SEQ ID NO:55, wherein said first peptide is crosslinked via a Cys-Cys bond to a second peptide to facilitate cellular uptake, wherein said second peptide comprises the amino acid sequence of SEQ ID NO:92.
16. The method of claim 15 , wherein said first peptide is crosslinked to said second peptide via an N-terminal Cys-Cys bond.