CELL PENETRATING PEPTIDES THAT INHIBIT IRF5 NUCLEAR LOCALIZATION
The invention provides inhibitors of interferon regulatory factor 5 (IRF5) nuclear localization and methods of using the inhibitors to treat autoimmune diseases such as systemic lupus erythematosus (SLE).
1 . A polypeptide comprising a cell penetrating peptide sequence and an interferon regulatory factor 5 (IRF5) nuclear localization signal (NLS) sequence, wherein the cell penetrating peptide sequence facilitates cellular uptake of the polypeptide.
2 . The polypeptide of claim 1 , wherein the polypeptide comprises formula (I):
X-Y-Z (I)
wherein X is a cell penetrating peptide sequence; Y is a linking group; and Z is an IRF5 NLS sequence.
3 . (canceled)
4 . The polypeptide of claim 1 , wherein the cell penetrating peptide sequence comprises a sequence at least 90% identical to
DRQIKIWFQNRRMKWKK (SEQ ID NO: 5), AAVALLPAVLLALLAP (SEQ ID NO: 9),
GRKKRRQRRRPPQ (SEQ ID NO: 10), CSIPPEVKFNKPFVYLI (SEQ ID NO: 11),
KKWKMRRNQFWVKVQRG (SEQ ID NO: 12), KLLKLLLKLWLKLLKLLL (SEQ ID
NO: 13), _INLKALAALAKKIL (SEQ ID NO: 14), RQIKIWFQNRRMKWKKGG (SEQ ID
NO: 15) or GWTLNSAGYLLGKINLKALAALAKKIL (SEQ ID NO: 16).
5 . The polypeptide of claim 4 , wherein the cell penetrating peptide sequence is selected from the group consisting of DRQIKIWFQNRRMKWKK (SEQ ID NO:5), AAVALLPAVLLALLAP (SEQ ID NO:9), GRKKRRQRRRPPQ (SEQ ID NO: 10), CSIPPEVKFNKPFVYLI (SEQ ID NO: 11), KKWKMRRNQFWVKVQRG (SEQ ID NO: 12), KLLKLLLKLWLKLLKLLL (SEQ ID NO: 13), INLKALAALAKKIL (SEQ ID NO: 14), RQIKIWFQNRRMKWKKGG (SEQ ID NO:15) and GWTLNSAGYLLGKINLKALAALAKKIL (SEQ ID NO: 16).
6 . (canceled)
7 . The polypeptide of claim 1 , wherein the IRF5 NLS sequence comprises a sequence at least 90% identical to PRRVRLK (SEQ ID NO: 1) or PREKKLI (SEQ ID NO:2).
8 . The polypeptide of claim 7 , wherein the IRF5 NLS sequence is PRRVRLK (SEQ ID NO: 1) or PREKKLI (SEQ ID NO:2).
9 - 10 . (canceled)
11 . The polypeptide of claim 1 , which comprises a sequence at least 90% identical to:
DRQIKIWFQNRRMKWKKPRRVRLK (SEQ ID NO: 3) or
DRQIKIWFQNRRMKWKKPREKKLI (SEQ ID NO: 4).
12 . (canceled)
13 . The polypeptide of claim 11 , which comprises a sequence at least 99% identical to SEQ ID NO:3 or SEQ ID NO:4.
14 . The polypeptide of claim 13 , which comprises SEQ ID NO:3 or SEQ ID NO:4.
15 - 19 . (canceled)
20 . The polypeptide of claim 1 , which polypeptide is an inhibitor of interferon regulatory factor 5 (IRF5).
21 . The polypeptide of claim 1 , which polypeptide is an inhibitor of interferon regulatory factor 5 (IRF5) nuclear localization.
22 - 25 . (canceled)
26 . The polypeptide of claim 1 , wherein the polypeptide comprises a chemical modification.
27 . A nucleic acid sequence encoding the polypeptide of claim 1 .
28 . A pharmaceutical composition that comprises a polypeptide of claim 1 and a pharmaceutically acceptable carrier.
29 . A method of inhibiting interferon regulatory factor 5 (IRF5) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a polypeptide of claim 1 .
30 . (canceled)
31 . A method for treating an autoimmune disease, classical Hodgkin lymphoma, atherosclerosis, cardiovascular disease, neuropathic pain, leukemia or lymphoma in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a polypeptide of claim 1 .
32 . The method of claim 31 , wherein the method is for treating an autoimmune disease, and wherein the autoimmune disease is systemic lupus erythematosus (SLE), systemic sclerosis (scleroderma), polymyositis/dermatomyositis, Crohn's disease, rheumatoid arthritis, periodontitis, SLE-associated atherosclerosis, Sjögren's syndrome, autoimmune encephalomyelitis, sarcoidosis, Behçet's disease, myasthenia gravis, lupus nephritis, inflammatory bowel disease, ankylosing spondylitis, primary biliary cirrhosis, colitis, juvenile idiopathic arthritis, pulmonary fibrosis, antiphospholipid syndrome, or psoriasis.
33 . The method of claim 32 , wherein the autoimmune disease is systemic lupus erythematosus (SLE).
34 . (canceled)
35 . The method of claim 31 , further comprising administering a second therapeutic agent.
36 - 47 . (canceled)
48 . A kit comprising a polypeptide as described in claim 1 , at least one other therapeutic agent, and instructions for administering the polypeptide and the other therapeutic agent(s) to an animal to treat an autoimmune disease, classical Hodgkin lymphoma, atherosclerosis, cardiovascular disease, neuropathic pain, leukemia or lymphoma.