APOE PEPTIDE DIMERS AND USES THEREOF
The present invention provides novel pharmaceutical compositions comprising ApoE-derived peptide dimers. In particular, the ApoE peptide dimers of the invention comprise at least two ApoE mimetic domains and can comprise one or more protein transduction domains. Methods of treating various conditions, such as cancer, inflammatory conditions, and neurodegenerative diseases, by administering the pharmaceutical compositions of the invention are also disclosed.
1 . A peptide dimer comprising a first ApoE peptide and a second ApoE peptide, wherein said first and second ApoE peptides are covalently linked by a linking moiety, and wherein the first and second ApoE peptides contain a sequence derived from amino acids 133-149 of ApoE protein.
2 . The peptide dimer of claim 1 , wherein said linking moiety is selected from the group consisting of a disulfide bridge, a bismaleimide, a 1,4-disubstituted triazole, and N,N-dipropargylamine.
3 . The peptide dimer of claim 2 , wherein said bismaleimide is bismaleimido-ethane or bismaleimido-hexane.
4 . The peptide dimer of claim 1 , wherein said first and second ApoE peptides are the same.
5 . The peptide dimer of claim 4 , wherein said first and second ApoE peptides are peptides having a sequence selected from the group consisting of LRVRLASHLRKLRKRLL (SEQ ID NO: 3), AS(Aib)LRKL(Aib)KRLL (SEQ ID NO: 5), LRVRLAS(Aib)LKRLRK(Nitro-Arg)LL (SEQ ID NO: 4), and LRVRLAS(Aib)LRKLR(K-Ac)RLL (SEQ ID NO: 35).
6 . The peptide dimer of claim 1 , wherein said first and second ApoE peptides are different.
7 . The peptide dimer of claim 1 , wherein said first ApoE peptide is conjugated to a first protein transduction domain through one or more first linking residues.
8 . The peptide dimer of claim 7 , wherein said first protein transduction domain is selected from the group consisting of peptides derived from antennapedia, TAT, SynB1, SynB3, SynB5, and polyarginine.
9 . The peptide dimer of claim 8 , wherein said first protein transduction domain has a sequence of RQIKIWFQNRRMKWKK (SEQ ID NO: 8), YGRKKRRQRRR (SEQ ID NO: 9), or WKK.
10 . The peptide dimer of claim 7 , wherein said one or more first linking residues is cysteine, azidohomoalanine, or propargylglycine.
11 . The peptide dimer of claim 7 , wherein said first and second ApoE peptides are peptides having a sequence selected from the group consisting of LRVRLASHLRLRKRLL (SEQ ID NO: 3), AS(Aib)LRKL(Aib)KRLL (SEQ ID NO: 5), LRVRLAS(Aib)LKRLRK(Nitro-Arg)LL (SEQ ID NO: 4), and LRVRLAS(Aib)LRKLR(K-Ac)RLL (SEQ ID NO: 35).
12 . The peptide dimer of claim 7 , wherein said second ApoE peptide is conjugated to a second protein transduction domain through one or more second linking residues.
13 . The peptide dimer of claim 12 , wherein said second protein transduction domain is selected from the group consisting of peptides derived from antennapedia, TAT, SynB1, SynB3, SynB5, and polyarginine.
14 . The peptide dimer of claim 13 , wherein said second protein transduction domain has a sequence of RQIKIWFQNRRMKWKK (SEQ ID NO: 8), YGRKKRRQRRR (SEQ ID NO: 9), or WKK.
15 . The peptide dimer of claim 12 , wherein said one or more second linking residues is cysteine, azidohomoalanine, or propargylglycine.
16 . The peptide dimer of claim 12 , wherein said first and second ApoE peptides are peptides having a sequence selected from the group consisting of LRVRLASHLRKLRKRLL (SEQ ID NO: 3), AS (Aib)LRKL(Aib)KRLL (SEQ ID NO: 5), LRVRLAS(Aib)LKRLRK(Nitro-Arg)LL (SEQ ID NO: 4), and LRVRLAS(Aib)LRKLR(K-Ac)RLL (SEQ ID NO: 35).
17 . A pharmaceutical composition comprising an effective amount of a peptide dimer of claim 1 and a pharmaceutically acceptable carrier.
18 . A method of treating cancer, CNS inflammation, traumatic brain injury, cerebral ischemia, cerebral edema, neurolathyrism, amyotrophic lateral sclerosis (ALS), Huntington's disease, Parkinson's disease, schizophrenia, atherosclerosis, bacterial sepsis, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, polyarticular-course juvenile rheumatoid arthritis, inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, or Alzheimer's disease in a subject in need thereof comprising administering to the subject a composition of claim 17 .
19 . The method of claim 18 , wherein said cancer is leukemia, lymphoma, or breast cancer.
20 . (canceled)
21 . The method of claim 19 , wherein said leukemia is chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), or acute lymphocytic leukemia (ALL).
22 - 43 . (canceled)