Modulators of antiviral signaling pathways and therapeutic uses thereof
The invention provides methods, compositions, and kits featuring novel RIG-I like receptor activators or inhibitors for use in preventing or treating virus infection or autoimmune disease.
1. An inhibitor of antiviral RIG-I like receptors (RLRs) activity comprising a polypeptide fragment of SEQ ID NO: 4, wherein the polypeptide fragment of SEQ ID NO: 4 is a fragment selected from the group consisting of residues 10-77 of SEQ ID NO: 4, residues 15-77 of SEQ ID NO: 4, residues 20-77 of SEQ ID NO: 4, residues 25-77 of SEQ ID NO: 4, residues 30-77 of SEQ ID NO: 4, residues 35-77 of SEQ ID NO: 4, residues 40-77 of SEQ ID NO: 4, residues 45-77 of SEQ ID NO: 4, residues 50-77 of SEQ ID NO: 4, residues 10-73 of SEQ ID NO: 4, residues 15-73 of SEQ ID NO: 4, residues 20-73 of SEQ ID NO: 4, residues 25-73 of SEQ ID NO: 4, residues 30-73 of SEQ ID NO: 4, residues 35-73 of SEQ ID NO: 4, residues 40-73 of SEQ ID NO: 4, residues 45-73 of SEQ ID NO: 4 and residues 50-73 of SEQ ID NO: 4, and a covalently linked moiety that facilitates delivery of the inhibitor to the cytosol of a cell.
2. The inhibitor of claim 1 , wherein the polypeptide fragment consists of SEQ ID NO: 1 (GNRDTLWHLFNTLQRRPGWVEYFI).
3. The inhibitor of claim 1 , wherein the inhibitor further comprises amino acids from the medial proline-rich region of SEQ ID NO: 4 (amino acids 107-173) or the C-terminal transmembrane domain of SEQ ID NO: 4 (amino acids 514-535).
4. The inhibitor of claim 1 , wherein the covalent linkage of the moiety is N-terminal to the polypeptide fragment.
5. The inhibitor of claim 1 , wherein the covalent linkage of the moiety is C-terminal to the peptide fragment.
6. The inhibitor of claim 1 , wherein the moiety comprises a cell penetrating domain of the Drosophila antennapedia protein.
7. The inhibitor of claim 6 , wherein the cell penetrating domain comprises SEQ ID NO: 2 (RQIKIWFQNRRMKWKK).
8. The inhibitor of claim 1 , wherein the inhibitor comprises SEQ ID NO: 3 (GNRDTLWHLFNTLQRRPGWVEYFIRQIKIWFQNRRMKWKK).
9. The inhibitor of claim 1 , wherein the inhibitor further comprises a detectable moiety.
10. A pharmaceutical composition comprising an inhibitor of claim 1 .
11. The pharmaceutical composition of claim 10 , wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier, diluent, or excipient.
12. The pharmaceutical composition of claim 10 , wherein the pharmaceutical composition further comprises a therapeutic agent.
13. The pharmaceutical composition of claim 12 , wherein the therapeutic agent is an antiviral agent or an immunosuppressive agent.
14. An isolated polynucleotide encoding the inhibitor of claim 1 .
15. An expression vector comprising the isolated polynucleotide of claim 14 .
16. A host cell comprising the expression vector of claim 15 .
17. A method of inhibiting RLR-induced signaling in a cell comprising contacting the cell with an inhibitor of claim 1 , thereby inhibiting the MAVS adaptor protein in the cell.
18. A method of inhibiting RLR-induced signaling in a subject, wherein the method comprises administering to the subject an effective amount of an inhibitor of claim 1 , thereby inhibiting the MAVS adaptor protein in the subject.
19. A method of treating a subject for a disease or disorder associated with an inappropriate host response to self RNA, wherein the method comprises administering an effective amount of an inhibitor of claim 1 , thereby inhibiting RLR-induced signaling in the subject and treating the disease or disorder.