Membrane-permeant peptide complexes for treatment of sepsis
Methods and compositions for treating sepsis using cell membrane-permeant peptide conjugate covalent compounds having target cell specificity are provided.
1. A method for treating sepsis comprising:
administering to a subject a therapeutically effective amount of a compound comprising:
a cell membrane-permeant peptide comprising a sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7;
a polypeptide comprising a BH4 anti-apoptotic homology domain of Bcl-xL; and
a linker moiety linking the cell membrane-permeant peptide and the polypeptide.
2. A method for treating sepsis comprising:
conjugating a cell membrane permeant peptide with a protein domain that regulates apoptosis in sepsis in at least one of lymphocytes, gut epithelial cells and dendritic cells, to form an anti-sepsis peptide conjugate; and
combining the peptide conjugate with a pharmaceutically acceptable carrier, excipient or diluent to form a pharmaceutical compound;
wherein
the cell membrane-permeant peptide comprises a sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7; and
the protein domain comprises a BH4 anti-apoptotic homology domain of Bcl-xL.
3. A method according to claim 2 further comprising administering a therapeutically effective amount of the pharmaceutically compound to a subject.
4. A method for the treatment of sepsis in a human subject comprising: providing a therapeutic composition comprising
a cell membrane-permeant peptide comprising a sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7; and
a polypeptide comprising a BH4 anti-apoptotic homology domain of Bcl-xL;
wherein,
the cell membrane-permeant peptide is conjugated to the Bcl-xL protein domain.
5. A method according to claim 4 further comprising administering said therapeutic composition to the human subject under conditions such that at least one symptom of sepsis is reduced.
6. The method of claim 1 , wherein the linker moiety is a non-functional linker moiety.
7. The method of claim 6 , wherein the non-functional linker moiety comprises aminohexanoic acid.
8. The method of claim 1 , wherein the linker moiety is a functional linker moiety.
9. The method of claim 2 , wherein the linker moiety is a non-functional linker moiety.
10. The method of claim 9 , wherein the non-functional linker moiety comprises aminohexanoic acid.
11. The method of claim 2 , wherein the linker moiety is a functional linker moiety.
12. The method of claim 4 , wherein the linker moiety is a non-functional linker moiety.
13. The method of claim 12 , wherein the non-functional linker moiety comprises aminohexanoic acid.
14. The method of claim 2 , wherein the linker moiety is a functional linker moiety.
15. The method of claim 1 , wherein the cell membrane-permeant peptide comprises a sequence of SEQ ID NO: 7.
16. The method of claim 1 wherein the polypeptide comprises a peptide having a sequence of SEQ ID NO: 40.
17. The method of claim 2 wherein the protein comprises a peptide having a sequence of SEQ ID NO: 40.
18. The method of claim 4 wherein the polypeptide comprises a peptide having a sequence of SEQ ID NO: 40.