Use of peptide-based inhibitors of the stat3-IL10 pathway for treating bacterial infection and granulomatous disease
The invention provides a method of treating pathogenic bacterial infection (e.g., tuberculosis infection) in an animal comprising administering a peptide-based inhibitor of the STAT3-IL10 pathway or a nucleic acid encoding the peptide-based inhibitor to the animal. The invention also provides methods of treating chronic granulomatous disease and Wegener's granulomatosis in an animal comprising administering a peptide-based inhibitor of the STAT3-IL10 pathway or a nucleic acid encoding the peptide-based inhibitor to the animal.
1. A method of treating an infection of Mycobacteriaceae sp. in an animal in need thereof, comprising administering a therapeutically effective amount of a peptide-based inhibitor of STAT3 or a nucleic acid encoding the peptide-based inhibitor to the animal,
wherein the peptide-based inhibitor comprises the amino acid sequence of any one of SEQ ID NOs: 40, 42, 44, 46, 48, 49, 55-57, 66-76, or the inverse sequence thereof, wherein:
SEQ ID NO: 40 is x 1 TRYLx 3 QLHKLY (SEQ ID NO: 40),
SEQ ID NO: 42 is x 1 TRYLx 3 QLHKLYx 6 (SEQ ID NO: 42),
SEQ ID NO: 44 is YLKHLQx 3 LYRTx 1 (SEQ ID NO: 44),
SEQ ID NO: 46 is x 6 YLKHLQx 3 LYRTx 1 (SEQ ID NO: 46),
wherein x 1 is D, A, or N, x 3 is E or Q, and x 6 is K, R, or S,
thereby treating the infection in the animal.
2. The method of claim 1 , wherein the Mycobacteriaceae sp. is Mycobacterium tuberculosis.
3. The method of claim 1 , wherein the peptide-based inhibitor comprises the amino acid sequence of SEQ ID NO: 65 (ST3-H2A2).
4. The method of claim 1 , wherein administering the peptide-based inhibitor to the animal results in reduced Mycobacterium tuberculosis (Mtb) bacilli load in the lungs of the animal.
5. The method of claim 1 , wherein the animal is undergoing sequential or simultaneous tuberculosis therapy.
6. The method of claim 5 , wherein the tuberculosis therapy is antibiotic treatment.
7. The method of claim 1 , wherein the animal is selected from the group consisting of mice, rats, horses, cows, sheep, dogs, cats, and primates.
8. The method of claim 7 , wherein the animal is a human.
9. The method of claim 1 , wherein the peptide-based inhibitor comprises D-amino acids.
10. The method of claim 1 , wherein the peptide-based inhibitor further comprises a cell-penetrating motif.
11. The method of claim 10 , wherein the cell-penetrating motif is a protein transduction domain or fatty acid, optionally attached to the peptide-based inhibitor via a linker sequence.
12. The method of claim 1 , wherein the peptide-based inhibitor comprises a terminal acetyl or palmitoyl group.
13. The method of claim 12 , wherein the peptide-based inhibitor comprises a terminal ε-palmitoyl modified lysine residue.
14. The method of claim 1 , wherein the nucleic acid is in the form of a vector.
15. The method of claim 1 , wherein the peptide-based inhibitor is administered in the form of a pharmaceutical composition.
16. The method of claim 1 , wherein the peptide-based inhibitor is administered as an inhalant.
17. A method of treating a disease selected from tuberculosis, Wegener's granulomatosis, and chronic granulomatous disease in an animal in need thereof, comprising administering a therapeutically effective amount of a peptide-based inhibitor of STAT3 or a nucleic acid encoding the peptide-based inhibitor to the animal,
wherein the peptide-based inhibitor comprises the amino acid sequence of any one of SEQ ID NOs: 40, 42, 44, 46, 48, 49, 55-57, 66-76, or the inverse sequence thereof, wherein:
SEQ ID NO: 40 is x 1 TRYLx 3 QLHKLY (SEQ ID NO: 40),
SEQ ID NO: 42 is x 1 TRYLx 3 QLHKLYx 6 (SEQ ID NO: 42),
SEQ ID NO: 44 is YLKHLQx 3 LYRTx 1 (SEQ ID NO: 44),
SEQ ID NO: 46 is x 6 YLKHLQx 3 LYRTx 1 (SEQ ID NO: 46),
wherein x 1 is D, A, or N, x 3 is E or Q, and x 6 is K, R, or S,
thereby treating the disease in the animal.
18. The method of claim 17 , wherein the disease is tuberculosis.
19. The method of claim 17 , wherein the disease is Wegener's granulomatosis.
20. The method of claim 17 , wherein the disease is chronic granulomatous disease.