INTERFERON REGULATORY FACTOR 5 INHIBITORS AND USES THEREOF
Polypeptides comprising a cell penetrating amino acid sequence and an interferon regulatory factor 5 (IRF5) targeting amino acid sequence are disclosed, where the IRF5 targeting amino acid sequence is one or more of RHATRHG (SEQ ID NO:1), KSRDFRL (SEQ ID NO:2) and GPRDMPP (SEQ ID NO:3), as well as methods of using these polypeptides to treat diseases, such as autoimmune and inflammatory diseases.
1 - 18 . (canceled)
19 . A nucleic acid sequence encoding a polypeptide comprising a cell penetrating amino acid sequence and an interferon regulatory factor 5 (IRF5) targeting amino acid sequence, wherein the polypeptide comprises amino acid sequence DRQIKIWFQNRRMKWKKRHATRHG (SEQ ID NO:17), or DRQIKIWFQNRRMKWKKKSRDFRL (SEQ ID NO:18) or DRQIKIWFQNRRMKWKKGPRDMPP (SEQ ID NO:19).
20 - 21 . (canceled)
22 . A method of inhibiting interferon regulatory factor 5 (IRF5) in a patient in need thereof, comprising administering to the patient a polypeptide in an amount effective to inhibit IRF5 in a patient, wherein the polypeptide consists of a cell penetrating amino acid sequence and an IRF5 targeting amino acid sequence, wherein the IRF5 targeting amino acid sequence consists of one or more of RHATRHG (SEQ ID NO:1), KSRDFRL (SEQ ID NO:2) and GPRDMPP (SEQ ID NO:3).
23 . (canceled)
24 . The method of claim 22 , wherein the polypeptide binds directly to IRF5 to inhibit IRF5 nuclear translocation.
25 . The method of claim 22 , wherein the patient has an autoimmune disease.
26 . The method of claim 25 , 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.
27 . The method of claim 25 , wherein the autoimmune disease is systemic lupus erythematosus (SLE).
28 . The method of claim 22 , wherein the patient has classical Hodgkin lymphoma, atherosclerosis, cardiovascular disease, neuropathic pain, leukemia (e.g., T cell large granular lymphocyte leukemia) or lymphoma.
29 - 32 . (canceled)
33 . The method of claim 22 , wherein the cell penetrating amino acid sequence comprises a sequence at least 90% identical to DRQIKIWFQNRRMKWKK (SEQ ID NO:4), AAVALLPAVLLALLAP (SEQ ID NO:5), GRKKRRQRRRPPQ (SEQ ID NO:6), CSIPPEVKFNKPFVYLI (SEQ ID NO:7), KKWKMRRNQFWVKVQRG (SEQ ID NO:8), KLLKLLLKLWLKLLKLLL (SEQ ID NO:9), INLKALAALAKKIL (SEQ ID NO:10), RQIKIWFQNRRMKWKKGG (SEQ ID NO:11), GWTLNSAGYLLGKINLKALAALAKKIL (SEQ ID NO:12), YLKFIPLKRAIWLIK (SEQ ID NO:13), MANLGYWLLALFVTMWTDVGLCKKRPKP (SEQ ID NO:14), RQIKIWFQNRRMKWKK (SEQ ID NO:15) or LCLRPVG (SEQ ID NO:16).
34 . The method of claim 22 , wherein the cell penetrating amino acid sequence comprises DRQIKIWFQNRRMKWKK (SEQ ID NO:4), AAVALLPAVLLALLAP (SEQ ID NO: 5), GRKKRRQRRRPPQ (SEQ ID NO:6), CSIPPEVKFNKPFVYLI (SEQ ID NO:7), KKWKMRRNQFWVKVQRG (SEQ ID NO:8), KLLKLLLKLWLKLLKLLL (SEQ ID NO:9), INLKALAALAKKIL (SEQ ID NO:10), RQIKIWFQNRRMKWKKGG (SEQ ID NO:11), GWTLNSAGYLLGKINLKALAALAKKIL (SEQ ID NO:12), YLKFIPLKRAIWLIK (SEQ ID NO: 13), MANLGYWLLALFVTMWTDVGLCKKRPKP (SEQ ID NO:14), RQIKIWFQNRRMKWKK (SEQ ID NO:15) or LCLRPVG (SEQ ID NO:16).
35 . The method of claim 22 , wherein the cell penetrating amino acid sequence is selected from the group consisting of DRQIKIWFQNRRMKWKK (SEQ ID NO:4), AAVALLPAVLLALLAP (SEQ ID NO:5), GRKKRRQRRRPPQ (SEQ ID NO:6), CSIPPEVKFNKPFVYLI (SEQ ID NO:7), KKWKMRRNQFWVKVQRG (SEQ ID NO:8), KLLKLLLKLWLKLLKLLL (SEQ ID NO:9), INLKALAALAKKIL (SEQ ID NO:10), RQIKIWFQNRRMKWKKGG (SEQ ID NO:11), GWTLNSAGYLLGKINLKALAALAKKIL (SEQ ID NO:12), YLKFIPLKRAIWLIK (SEQ ID NO:13), MANLGYWLLALFVTMWTDVGLCKKRPKP (SEQ ID NO:14), RQIKIWFQNRRMKWKK (SEQ ID NO:15) and LCLRPVG (SEQ ID NO:16).
36 . The method of claim 22 , wherein the polypeptide comprises an amino acid sequence at least 90% identical to DRQIKIWFQNRRMKWKKRHATRHG (SEQ ID NO:17), DRQIKIWFQNRRMKWKKKSRDFRL (SEQ ID NO:18) or DRQIKIWFQNRRMKWKKGPRDMPP (SEQ ID NO:19).
37 . The method of claim 22 , wherein the polypeptide comprises amino acid sequence DRQIKIWFQNRRMKWKKRHATRHG (SEQ ID NO:17), DRQIKIWFQNRRMKWKKKSRDFRL (SEQ ID NO:18) or DRQIKIWFQNRRMKWKKGPRDMPP (SEQ ID NO:19).
38 . The method of claim 22 , wherein the polypeptide consists of an amino acid sequence at least 90% identical to DRQIKIWFQNRRMKWKKRHATRHG (SEQ ID NO:17), DRQIKIWFQNRRMKWKKKSRDFRL (SEQ ID NO:18) or DRQIKIWFQNRRMKWKKGPRDMPP (SEQ ID NO:19).
39 . The method of claim 22 , wherein the polypeptide consists of amino acid sequence DRQIKIWFQNRRMKWKKRHATRHG (SEQ ID NO:17), DRQIKIWFQNRRMKWKKKSRDFRL (SEQ ID NO:18) or DRQIKIWFQNRRMKWKKGPRDMPP (SEQ ID NO:19).