Compositions and methods for CaMKII inhibitors and uses thereof
View Patent ↗Embodiments herein generally relate to methods, compositions and uses of CaMKII inhibitors. Other embodiments relate to methods, compositions and uses of agents that target CaMKII. Yet further embodiments relate to compositions, methods and uses of CaMKIIN-derived molecules and other CaMKII inhibitor molecules that inhibit autonomous CaMKII activity. In accordance with these embodiments, compositions that inhibit autonomous CaMKII activity may be used for treating conditions causing neuronal cell death, for treating cancer or for treating neurodegenerative disorders.
1. A purified polypeptide comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 28, wherein the purified polypeptide is a derivative of CaMKIIN and comprises the following amino acid substitutions:
amino acid at position two of SEQ ID NO: 28 is alanine;
amino acid at position three of SEQ ID NO: 28 is alanine, arginine or lysine;
amino acid at position five of SEQ ID NO: 28 is arginine;
amino acid at position seven of SEQ ID NO: 28 is alanine, arginine or lysine;
amino acid at position eight of SEQ ID NO: 28 is alanine or lysine;
amino acid at position nine of SEQ ID NO: 28 is leucine;
amino acid at position twelve of SEQ ID NO: 28 is arginine, glutamine or valine;
amino acid at position thirteen of SEQ ID NO: 28 is alanine;
amino acid at position fourteen of SEQ ID NO: 28 is alanine;
amino acid at position fifteen of SEQ ID NO: 28 is isoleucine or phenylalanine;
amino acid at position sixteen of SEQ ID NO: 28 is alanine, aspartic acid or glutamic acid; and
amino acid at position seventeen of SEQ ID NO: 28 is arginine.
2. The purified polypeptide of claim 1 , wherein the purified polypeptide further comprises a cell-transfer/penetrating agent associated with the peptide.
3. The purified polypeptide of claim 2 , wherein the cell-transfer/penetrating agent comprises tat, ant, a meristyl-group, a palmityl-group or a combination thereof.
4. The purified polypeptide of claim 1 , wherein the polypeptide comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 28.
5. The purified polypeptide of claim 1 , wherein the amino acid at position three of SEQ ID NO: 28 is alanine, and wherein the purified polypeptide has increased potency of CaMKII inhibition compared to a wild type CaMKIIN.
6. A pharmaceutical composition comprising:
a purified polypeptide of claim 1 ; and
a pharmaceutically acceptable derivative or salt thereof.
7. The pharmaceutical composition of claim 6 , wherein the composition further comprises a cell-transfer/penetrating agent associated with the purified polypeptide.
8. The pharmaceutical composition of claim 7 , wherein the cell-transfer/penetrating agent comprises tat, ant, meristyl-group, palmityl-group or combination thereof.
9. A cultured cell comprising a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence represented by SEQ ID NO: 28, wherein the purified polypeptide is from CaMKIIN and comprises the following amino acid substitutions:
amino acid at position two of SEQ ID NO: 28 is alanine;
amino acid at position three of SEQ ID NO: 28 is alanine, arginine or lysine;
amino acid at position five of SEQ ID NO: 28 is arginine;
amino acid at position seven of SEQ ID NO: 28 is alanine, arginine or lysine;
amino acid at position eight of SEQ ID NO: 28 is alanine or lysine;
amino acid at position nine of SEQ ID NO: 28 is leucine;
amino acid at position twelve of SEQ ID NO: 28 is arginine, glutamine or valine;
amino acid at position thirteen of SEQ ID NO: 28 is alanine;
amino acid at position fourteen of SEQ ID NO: 28 is alanine;
amino acid at position fifteen of SEQ ID NO: 28 is isoleucine or phenylalanine;
amino acid at position sixteen of SEQ ID NO: 28 is alanine, aspartic acid or glutamic acid; and
amino acid at position seventeen of SEQ ID NO: 28 is arginine.
10. A method of reducing or eliminating CaMKII activity in a cell, the method comprising:
exposing the cell to a purified polypeptide comprising an amino acid sequence at least 95% identical to SEQ ID NO: 28, wherein the purified polypeptide is a derivative of CaMKIIN and comprises the following amino acid substitutions:
amino acid at position two of SEQ ID NO: 28 is alanine;
amino acid at position three of SEQ ID NO: 28 is alanine, arginine or lysine;
amino acid at position five of SEQ ID NO: 28 is arginine;
amino acid at position seven of SEQ ID NO: 28 is alanine, arginine or lysine;
amino acid at position eight of SEQ ID NO: 28 is alanine or lysine;
amino acid at position nine of SEQ ID NO: 28 is leucine;
amino acid at position twelve of SEQ ID NO: 28 is arginine, glutamine or valine;
amino acid at position thirteen of SEQ ID NO: 28 is alanine;
amino acid at position fourteen of SEQ ID NO: 28 is alanine;
amino acid at position fifteen of SEQ ID NO: 28 is isoleucine or phenylalanine;
amino acid at position sixteen of SEQ ID NO: 28 is alanine, aspartic acid or glutamic acid; and
amino acid at position seventeen of SEQ ID NO: 28 is arginine; and
wherein exposing the cell to the purified polypeptide reduces or eliminates CaMKII activity in the cell.
11. The method of claim 10 , wherein the cell is a neuronal cell and reducing or eliminating CaMKII activity in the neuronal cell prolongs survival of the neuronal cell.
12. The method of claim 10 , wherein the polypeptide further comprises a cell-transfer/penetrating agent associated with the peptide.
13. The method of claim 12 , wherein the cell-transfer/penetrating agent comprises tat, ant, meristyl-group, palmityl-group or combination thereof.
14. The method of claim 10 , wherein exposing the cell comprises treating a subject with a pharmaceutical composition comprising the purified polypeptide and a pharmaceutically acceptable derivative or salt thereof; and wherein treating the subject with the pharmaceutical composition reduces neuronal cell death in the subject.