USE OF PYRENE TO CARRY PEPTIDES ACROSS THE BLOOD BRAIN BARRIER
Described are methods for delivering a peptide agent across the blood-brain barrier, comprising administering to a subject a conjugate comprising (i) a peptide agent and pyrene, and related detection and therapeutic methods.
1 . A method for delivering a peptide agent across the blood-brain barrier, comprising administering to a subject a conjugate comprising:
peptide agent; and
pyrene.
2 . The method of claim 1 , wherein the peptide agent is a therapeutic agent or a detection agent.
3 . The method of claim 2 , wherein the peptide agent is capable of identifying a target protein associated with a neurological condition.
4 . The method of claim 3 , wherein the peptide agent selectively binds to a protein or structure associated with a neurological condition.
5 . The method of claim 4 , wherein the peptide agent includes an amino acid sequence corresponding to a region of the target protein which undergoes a conformational shift from an alpha-helical conformation to a beta-sheet conformation, but does not include the full-length sequence of the target protein.
6 . The method of claim 5 , wherein the detection agent comprises SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5 or SEQ ID NO:6.
7 . The method of claim 4 , wherein the peptide agent is an antibody specific for a protein or structure associated with a neurological condition.
8 . The method of claim 2 , wherein the peptide agent is a therapeutic agent useful for treating a neurological condition.
9 . The method of claim 1 , wherein the conjugate further comprises a detectable label.
10 . The method of claim 1 , wherein the pyrene is a derivative of pyrene.
11 . The method of claim 9 , wherein the derivative of pyrene is selected from the group consisting of alkyl pyrene, amino pyrene, pyrene carboxylate, pyrene butyrate, albumin-pyrene, PEGylated pyrene, a pyrene derivative comprising a free carboxyl group and a pyrene derivative comprising a free amine group.
12 . The method of claim 1 , wherein the conjugate comprises two or more pyrene moieties.
13 . The method of claim 1 , wherein conjugate exhibits enhanced permeability across the blood brain barrier as compared to the peptide.
14 . An in vivo detection method comprising
(a) administering to a subject a conjugate comprising (i) a peptide detection agent and (ii) pyrene and
(b) detecting conjugate localized in the brain of the subject.
15 . The method of claim 14 , wherein the conjugate comprises two or more pyrene moieties.
16 . The method of claim 14 , wherein the peptide detection agent is conjugated to pyrene at a position selected from at least one of the C-terminus and the N-terminus of the peptide detection agent.
17 . The method of claim 16 , wherein the peptide detection agent is conjugated to pyrene moieties at each of the C-terminus and N-terminus of the peptide detection agent.
18 . The method of claim 17 , wherein step (b) comprises detecting pyrene excimer formation.
19 . The method of claim 15 , wherein at least one pyrene moiety is a pyrene derivative comprising a free carboxyl group and at least one pyrene moiety is a pyrene derivative comprising a free amine group.
20 . The method of claim 14 , wherein the peptide detection agent is capable of identifying a protein or structure associated with a neurological condition.
21 . The method of claim 14 , wherein peptide detection agent is capable of identifying a protein in a specific conformation or state of self-aggregation.
22 . The method of claim 14 , wherein the detection agent comprises SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5 or SEQ ID NO:6.
23 . The method of claim 14 , wherein the conjugate further comprises a detectable label.
24 . The method of claim 23 , wherein the label is selected from the group consisting of fluorophores, MRI contrast agents, ion emitters, and radioactive labels.
25 . A method of treating a neurological condition, comprising administering to a subject in need thereof a therapeutically effective amount of a conjugate comprising (i) a peptide therapeutic agent and (ii) pyrene.
26 . The method of claim 25 , wherein the peptide therapeutic agent is useful in treating a neurological condition.
27 . The method of claim 25 , wherein the peptide therapeutic agent is an anti-amyloid agent.