APO E analogs and methods for their use
Novel ApoE-protein transduction domain conjugates are disclosed which are useful for treating disorders including CNS inflammation, traumatic brain injury, cerebral ischema, Alzheimer's Disease and other brain disorders.
1. An α-helical peptide derivative of ApoE fragment COG133 (SEQ ID NO: 1) consisting of no more than about 50 amino acids, wherein said α-helical peptide derivative comprises a sequence corresponding to at least amino acids 138-149 of ApoE and having at least one substitution of amino acids at positions 138, 140, 141, 145 or 148, wherein S139, R142, K143, L144, K146, R147 and L149 are unchanged, and wherein said α-helical peptide derivative is effective in a mouse traumatic brain injury (TBI) model over a greater therapeutic window as compared to a peptide having a sequence of SEQ ID NO: 1.
2. The α-helical peptide derivative of claim 1 , wherein said gain in therapeutic window as compared to COG133 is four-fold.
3. The α-helical peptide derivative of claim 1 , wherein said gain in therapeutic window as compared to COG133 is five-fold.
4. The α-helical peptide derivative of claim 1 , wherein said peptide derivative shows efficacy over COG133 at 60 minutes post-TBI.
5. The α-helical peptide derivative of claim 1 , wherein said peptide derivative shows efficacy over COG133 at 90 minutes post-TBI.
6. The α-helical peptide derivative of claim 1 , wherein said peptide derivative shows efficacy over COG133 at 150 minutes post-TBI.
7. The α-helical peptide derivative of claim 1 , wherein said peptide derivative shows efficacy over COG133 at 180 minutes post-TBI.
8. The α-helical peptide derivative of claim 1 , wherein said peptide derivative also exhibits a gain in therapeutic index as compared to COG133.
9. The α-helical peptide derivative of claim 1 , wherein said peptide derivative contains a sequence selected from the group consisting of:
(SEQ. ID. NO.3)
Ac-ASH-Aib-RKLRKRLL-NH 2
(SEQ. ID. NO.4)
Ac-AS-Aib-LRKLRKRLL-NH 2
(SEQ. ID. NO.5)
Ac-DS-Aib-LRKLRKRLL-NH 2
(SEQ. ID. NO.6)
Ac-ASH LRKL-AIb-KRLL-NH 2
(SEQ. ID. NO.7)
Ac-AS-Aib-LRKL-Aib-KRLL-NH 2
(SEQ. ID. NO.8)
Ac-DR-Aib-ASHLRKLRKR-Aib-L-NH 2
(SEQ. ID. NO.9)
Ac-DS-Aib-LRKLRKR-Aib-L-NH 2
(SEQ. ID. NO.10)
Ac-DR-Aib-ASHLRKL-Aib-KRLL-NH 2
(SEQ. ID. NO.11)
Ac-DS-Aib-LRKL-Aib-KRLL-NH 2
(SEQ. ID. NO.12)
Ac-DR- Aib-AS-Aib-LRKLRKRLL-NH 2
(SEQ. ID. NO.13)
Ac-DR-Aib-ASHLRKLRKRLL-NH 2
(SEQ. ID. NO.14)
Ac-CAS-Aib-LRKL-Aib-KRLL-NH 2
(SEQ. ID. NO.15)
Ac-DS-Aib-LRKL-Aib-KRLL-NH 2
(SEQ. ID. NO.16)
Ac-AS-Aib-LRKL-Aib-KRLV-NH 2
(SEQ. ID. NO.17)
Ac-AS-Aib-LRKL-Aib-KRLM-NH 2
(SEQ. ID. NO.18)
Ac-AS-Aib-LRKL-Aib-KRLI-NH 2
(SEQ. ID. NO.19)
Ac-AS-Aib-LRKL-Aib-KRLA-NH 2
(SEQ. ID. NO.28)
Ac-ASH-Aib-RKL-Aib-KRLL-NH 2
(SEQ. ID. NO.30)
Ac-AS-Aib-LRKL-Aib-KR-(NLe)-L-NH 2
(SEQ. ID. NO.45)
Ac-ASHCRKLCKRLL-NH 2
(SEQ. ID. NO.46)
AC-ASCLRKLCKRLL-NH 2
(SEQ. ID. NO.47)
Ac-CSHLRKLCKRLL-NH 2
and
(SEQ. ID. NO.49)
AC-ASHCRKLRKRCL-NH 2 ,
wherein Aib is amino iso-butyric acid, (NLe) is neurleucine, and Ac is an acelyated amino terminus.
10. A pharmaceutical composition comprising the α-helical peptide derivative of claim 1 .
11. A method of reducing glial activation, microglial activation or neuronal cell death by administering to a subject in need thereof the pharmaceutical composition of claim 10 .
12. The method of claim 11 , wherein said microglial activation is associated with CNS inflammation, traumatic brain injury, cerebral ischemia or cerebral edema.
13. The method of claim 11 , wherein said neuronal cell death is associated with glutamate excitotoxicity or N-methyl-D-aspartate (NMDA) exposure.
14. A method of treating atherosclerosis or of reducing the formation of atherosclerotic plaques by administering to a subject in need thereof the pharmaceutical composition of claim 10 .
15. A method of treating or ameliorating the symptoms of bacterial sepsis by administering to a subject in need thereof the pharmaceutical composition of claim 10 .
16. A method of treating or ameliorating the symptoms of multiple sclerosis by administering to a subject in need thereof the pharmaceutical composition of claim 10 .
17. A method of treating or ameliorating the symptoms of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or polyarticular-course juvenile rheumatoid arthritis by administering to a subject in need thereof the pharmaceutical composition of claim 10 .
18. A method of treating or ameliorating the symptoms of inflammatory bowel disease (IBD), Crohn's disease, or ulcerative colitis by administering to a subject in need thereof the pharmaceutical composition of claim 10 .
19. The α-helical peptide derivative of claim 1 , wherein said peptide derivative is linked to from one to fifteen additional amino acids or amino acid analogues at the N-terminus or C-terminus or both the N-and C-terminus, wherein such additional amino acids do not adversely affect the therapeutic function of the peptide.
20. A composition comprising the α-helical peptide derivative of claim 1 conjugated to a protein transduction domain (PTD).
21. The composition of claim 20 , wherein said PTD is derived from antennapedia.
22. A composition comprising a peptide consisting of less than about 50 amino acids comprising the sequence of peptide COG133 (SEQ ID NO: 1) or a peptide consisting of the sequence of peptide COG133 (SEQ ID NO: 1), wherein said peptide is conjugated to a PTD derived from antennapedia.
23. A pharmaceutical composition comprising the peptide of claim 22 .
24. The composition of claim 21 wherein said PTD is conjugated to the amino terminus of the peptide derivative.
25. The composition of claim 24 , wherein said PTD derived from antennapedia is RQIKIWFQNRRMKWKK (SEQ. ID. NO: 51) or RRMKWKK (SEQ. ID. NO: 52).
26. A method of treating, or ameliorating traumatic brain injury comprising administering to a subject in need thereof, the pharmaceutical composition of claim 10 .
27. The method of claim 26 , wherein the traumatic brain injury causes neurologic deficits in said subject.
28. The method of claim 26 , wherein the treatment comprises neurological recovery.
29. The method of claim 26 , wherein the treatment is improved cognitive function.
30. The method of claim 26 , wherein the traumatic brain injury is CNS inflammation or CNS edema.
31. A method of reducing macrophage activation by administering to a subject in need thereof the pharmaceutical composition of claim 10 .
32. The method of claim 31 , wherein said macrophage activation is associated with the formation of atherosclerotic plaques.
33. The composition of claim 22 wherein said PTD is conjugated to the amino terminus of the peptide comprising COG133.
34. The composition of claim 33 , wherein said PTD derived from antennapedia is RQIKIWFQNRRMKWKK (SEQ. ID. NO: 51) or RRMKWKK (SEQ. ID. NO: 52).
35. The α-helical peptide derivative of claim 1 , wherein said at least one amino acid substitution is a substitution with an amino iso-butyric acid (Aib) residue.
36. The composition of claim 34 , wherein said peptide conjugate consists of the sequence RQIKIWFQNRRMKWKK-LRVRLASHLRKLRKRLL (SEQ. ID. NO. 66).
37. The α-helical peptide derivative of claim 1 , wherein said α-helical peptide derivative comprises the sequence Ac-AS-Aib-LRKL-Aib-KRLL-NH 2 (SEQ. ID. NO. 7).