Method of treatment
The present invention relates generally to the field of immunomodulation. Taught herein is an agent for inhibiting immunostimulation mediated by a Toll-like receptor useful in the treatment of viral and microbial pathogenesis, diseases involving elements of autoimmunity and inflammation as well as cancer. The agent antagonizes disulfide bond formation between C98 and C475 of Toll-like receptor 7 (TLR7) thereby preventing TLR7 activation. Pharmaceutical compositions are also enabled herein.
1. A method for inhibiting TLR7-mediated immunostimulatory activity in a TLR7-expressing cell, the method comprising contacting the cell with a peptide of up to 190 amino acids in length, wherein the peptide comprises the amino acid sequence of DX 1 RCNCX 2 PX 3 X 4 (SEQ ID NO:27) wherein:
X 1 is L, F, or M;
X 2 is V or I;
X 3 is V, I, A, or P; and
X 4 is P, L, K, or R.
2. The method of claim 1 , wherein the peptide comprises the amino acid sequence DFRCNCVPIP (SEQ ID NO:26).
3. The method of claim 1 , wherein the peptide comprises the amino acid sequence DLRCNCVPVL (SEQ ID NO:1).
4. The method of claim 1 , wherein the peptide further comprises a moiety attached to the N-terminal or C-terminal end of the peptide which enables uptake of the peptide into the cell.
5. The method of claim 4 , wherein the moiety is a hydrophilic peptide, an amphiphilic peptide, a peptide with a periodic amino acid sequence, or a conjugate with cholestanol.
6. The method of claim 4 , wherein the moiety is a hydrophilic peptide selected from the group consisting of TAT (SEQ ID NO:2), SynB1 (SEQ ID NO:3), SynB3 (SEQ ID NO:4), PTD-4 (SEQ ID NO:5), PTD-5 (SEQ ID NO:6), FHV coat (SEQ ID NO:7), BMV Gag-(7-25) (SEQ ID NO:8), HTLV-II Rex-(4-16) (SEQ ID NO:9), D-Tat (SEQ ID NO:10), and R9-Tat (SEQ ID NO:11).
7. The method of claim 4 , wherein the moiety is an amphiphilic peptide selected from the group consisting of Transportan chimera (SEQ ID NO:12), MAP (SEQ ID NO:13), SBP (SEQ ID NO:14), FBP (SEQ ID NO:15), MPG [MPGac] (SEQ ID NO:16), MPG (ΔNLS) (SEQ ID NO:17), Pep-1 (SEQ ID NO:18), and Pep-2 (SEQ ID NO:19).
8. The method of claim 4 , wherein the moiety is a periodic amino acid sequence comprising a polyarginine or a polylysine sequence.
9. The method of claim 1 , wherein the peptide is up to 100 amino acids in length.
10. The method of claim 1 , wherein the peptide is up to 40 amino acids in length.
11. The method of claim 1 , wherein the cell is of a subject with an autoimmune disease, a viral pathogenesis, a microbial pathogenesis, an inflammation, or a cancer.
12. The method of claim 1 , wherein the cell is of a subject with a viral pathogenesis.
13. The method of claim 1 , wherein the cell is selected from macrophages, neutrophils, dendritic cells, natural killer cells, mast cells, eosinophils, basophils, B-lymphocytes, T-lymphocytes, and epithelial cells.
14. The method of claim 1 , wherein the cell is a macrophage.