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 each of said first and second ApoE peptides is no more than 20 amino acids in length and comprises a sequence selected from the group consisting of CLRVRLASHLRKLRKRLL (SEQ ID NO: 15), CAS(Aib)LRKL(Aib)KRLL (SEQ ID NO: 16), CLRVRLAS(Aib)LKRLRK(Nitro-Arg)LL (SEQ ID NO: 17), and CLRVRLAS(Aib)LRKLR(K-Ac)RLL (SEQ ID NO: 18), wherein the first and second ApoE peptides are covalently cross-linked through the cysteine residue at each amino terminus via a bismaleimide linker.
2. The peptide dimer of claim 1 , wherein said bismaleimide is bismaleimido-ethane or bismaleimido-hexane.
3. The peptide dimer of claim 1 , wherein said first and second ApoE peptides are the same.
4. The peptide dimer of claim 1 , wherein said first and second ApoE peptides are different.
5. 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.
6. The peptide dimer of claim 5 , wherein said first protein transduction domain is selected from the group consisting of peptides derived from antennapedia, TAT, SynB1, SynB3, SynB5, and polyarginine.
7. The peptide dimer of claim 6 , wherein said first protein transduction domain has a sequence of RQIKIWFQNRRMKWKK (SEQ ID NO: 8), YGRKKRRQRRR (SEQ ID NO: 9), or WKK.
8. The peptide dimer of claim 5 , wherein said one or more first linking residues is cysteine, azidohomoalanine, or propargylglycine.
9. The peptide dimer of claim 5 , wherein said second ApoE peptide is conjugated to a second protein transduction domain through one or more second linking residues.
10. The peptide dimer of claim 9 , wherein said second protein transduction domain is selected from the group consisting of peptides derived from antennapedia, TAT, SynB1, SynB3, SynB5, and polyarginine.
11. The peptide dimer of claim 10 , wherein said second protein transduction domain has a sequence of RQIKIWFQNRRNIKWKK (SEQ ID NO: 8), YGRKKRRQRRR (SEQ ID NO: 9), or WKK.
12. The peptide dimer of claim 9 , wherein said one or more second linking residues is cysteine, azidohomoalanine, or propargylglycine.
13. A pharmaceutical composition comprising an effective amount of a peptide dimer of claim 1 and a pharmaceutically acceptable carrier.
14. The peptide dimer of claim 1 , wherein said first ApoE peptide is conjugated to a first protein transduction domain through a first cysteine residue, said second ApoE peptide is conjugated to a second protein transduction domain through a second cysteine residue, wherein each of said first and second protein transduction domains has a sequence of RQIKIWFQNRRMKWKK (SEQ ID NO: 8) and is conjugated to the amino terminal end of each first and second ApoE peptides, and wherein each said first and second ApoE peptides has a sequence of CLRVRLASHLRKLRKRLL (SEQ ID NO: 15).