US2019322723A1PendingUtilityA1
Peptide-Mediated Non-Covalent Delivery of Active Agents Across the Blood-Brain Barrier
Assignee: MAYO FOUND MEDICAL EDUCATION & RESPriority: Jul 14, 2009Filed: Jul 3, 2019Published: Oct 24, 2019
Est. expiryJul 14, 2029(~3 yrs left)· nominal 20-yr term from priority
Inventors:Geoffry L. CurranGobinda SarkarJoseph F. PodusloRobert B. JenkinsVal J. LoweEric W. Mahlum
A61P 31/18A61P 25/16A61P 35/00A61P 25/00A61P 25/08A61P 25/28A61K 49/0058C07K 14/775A61K 51/12C12Y 302/01023A61K 47/64A61K 38/47A61K 49/0056A61K 51/088A61K 51/1018A61K 39/39533Y02A50/30
57
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
The peptides described herein can function as carrier peptides. These peptides can associate with (e.g., non-covalently bind) biologically active molecules or imaging agents to transport the biologically active molecules or imaging across the blood-brain barrier. In some cases, such transport may increase the effectiveness of the biological molecules or imaging agents.
Claims
exact text as granted — not AI-modified1 . (canceled)
2 . A method of transporting a nerve growth factor across the blood-brain barrier of a subject, the method comprising administering to the subject a complex, or a pharmaceutically acceptable salt thereof, comprising the biologically active molecule or imaging agent associated with a carrier peptide; wherein the carrier peptide comprises the sequence:
X n —[B] m
or a pharmaceutically acceptable salt thereof, wherein:
X is a hydrophilic amino acid;
B is a blood-brain barrier agent;
n is an integer from 4 to 50; and
m is integer from 1 to 3.
3 . The method of claim 2 , wherein each X is independently chosen from arginine, asparagine, aspartic acid, glutamic acid, glutamine, lysine, serine, threonine, and tyrosine.
4 . The method of claim 3 , wherein n is chosen from 4, 8, 12, 16, and 20.
5 . The method of claim 4 , wherein n is 16.
6 . The method of claim 2 , wherein m is 1.
7 . The method of claim 2 , wherein the nerve growth factor is non-covalently bound to the carrier peptide.
8 . The method of claim 2 , wherein the blood-brain barrier agent comprises a receptor binding domain of an apolipoprotein is chosen from the receptor binding domain of ApoA, ApoB, ApoC, ApoD, ApoE, ApoE2, ApoE3, and ApoE4.
9 . The method of claim 2 , wherein B comprises the sequence:
(SEQ ID NO: 29)
L-R-X1-R-X2-X3-X4-H-L-R-X5-X6-X7-K-R-L-X8-R-D-X9
wherein:
X1 is selected from the group consisting of A, L, S, and V;
X2 is selected from the group consisting of L and M;
X3 is selected from the group consisting of A and S;
X4 is selected from the group consisting of N, S, and T;
X5 is selected from the group consisting of K and N;
X6 is selected from the group consisting of L, M, and V;
X7 is selected from the group consisting of R and P;
X8 is selected from the group consisting of L and M; and
X9 is selected from the group consisting of A and L.
10 . The method of claim 9 , wherein the carrier peptide comprises the sequence:
(SEQ ID NO: 143)
[X] n -L-R-X1-R-X2-X3-X4-H-L-R-X5-X6-X7-K-R-L-X8-R-
D-X9
wherein:
X is lysine.
11 . The method of claim 10 , wherein the carrier peptide comprises the sequence:
(SEQ ID NO: 19)
K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A;
(SEQ ID NO: 20)
K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-L-
R-D-A;
(SEQ ID NO: 21)
K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-R-
K-R-L-L-R-D-A;
(SEQ ID NO: 22)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-
R-K-L-R-K-R-L-L-R-D-A;
(SEQ ID NO: 23)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-
A-S-H-L-R-K-L-R-K-R-L-L-R-D-A;
(SEQ ID NO: 46)
K-K-K-K-L-R-S-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A;
(SEQ ID NO: 47)
K-K-K-K-K-K-K-K-L-R-S-R-L-A-S-H-L-R-K-L-R-K-R-L-L-
R-D-A;
(SEQ ID NO: 48)
K-K-K-K-K-K-K-K-K-K-K-K-L-R-S-R-L-A-S-H-L-R-K-L-R-
K-R-L-L-R-D-A;
(SEQ ID NO: 49)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-S-R-L-A-S-H-L-
R-K-L-R-K-R-L-L-R-D-A;
(SEQ ID NO: 50)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-S-R-L-
A-S-H-L-R-K-L-R-K-R-L-L-R-D-A ;
(SEQ ID NO: 51)
K-K-K-K-L-R-V-R-M-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A;
(SEQ ID NO: 52)
K-K-K-K-K-K-K-K-L-R-V-R-M-A-S-H-L-R-K-L-R-K-R-L-L-
R-D-A;
(SEQ ID NO: 53)
K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-M-A-S-H-L-R-K-L-R-
K-R-L-L-R-D-A;
(SEQ ID NO: 54)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-M-A-S-H-L-
R-K-L-R-K-R-L-L-R-D-A;
(SEQ ID NO: 55)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-M-
A-S-H-L-R-K-L-R-K-R-L-L-R-D-A;
(SEQ ID NO: 56)
K-K-K-K-L-R-V-R-L-A-T-H-L-R-K-L-R-K-R-L-L-R-D-A;
(SEQ ID NO: 57)
K-K-K-K-K-K-K-K-L-R-V-R-L-A-T-H-L-R-K-L-R-K-R-L-L-
R-D-A;
(SEQ ID NO: 58)
K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-T-H-L-R-K-L-R-
K-R-L-L-R-D-A;
(SEQ ID NO: 59)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-T-H-L-
R-K-L-R-K-R-L-L-R-D-A;
(SEQ ID NO: 60)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-
A-T-H-L-R-K-L-R-K-R-L-L-R-D-A;
(SEQ ID NO: 61)
K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-P-K-R-L-L-R-D-A;
(SEQ ID NO: 62)
K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-P-K-R-L-L-
R-D-A;
(SEQ ID NO: 63)
K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-P-
K-R-L-L-R-D-A;
(SEQ ID NO: 64)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-
R-K-L-P-K-R-L-L-R-D-A;
(SEQ ID NO: 65)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-
A-S-H-L-R-K-L-P-K-R-L-L-R-D-A;
(SEQ ID NO: 66)
K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-M-R-D-A;
(SEQ ID NO: 67)
K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-R-K-R-L-M-
R-D-A;
(SEQ ID NO: 68)
K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-L-R-
K-R-L-M-R-D-A;
(SEQ ID NO: 69)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-
R-K-L-R-K-R-L-M-R-D-A;
(SEQ ID NO: 70)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-
A-S-H-L-R-K-L-R-K-R-L-M-R-D-A;
(SEQ ID NO: 71)
K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-L-R-K-R-L-L-R-D-A;
(SEQ ID NO: 72)
K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-L-R-K-R-L-L-
R-D-A;
(SEQ ID NO: 73)
K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-L-R-
K-R-L-L-R-D-A;
(SEQ ID NO: 74)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-
R-N-L-R-K-R-L-L-R-D-A;
(SEQ ID NO: 75)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-
A-S-H-L-R-N-L-R-K-R-L-L-R-D-A;
(SEQ ID NO: 76)
K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-V-R-K-R-L-L-R-D-A;
(SEQ ID NO: 77)
K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-V-R-K-R-L-L-
R-D-A;
(SEQ ID NO: 78)
K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-V-R-
K-R-L-L-R-D-A;
(SEQ ID NO: 79)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-
R-K-V-R-K-R-L-L-R-D-A;
(SEQ ID NO: 80)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-
A-S-H-L-R-K-V-R-K-R-L-L-R-D-A;
(SEQ ID NO: 81)
K-K-K-K-L-R-V-R-M-S-S-H-L-R-K-L-R-K-R-L-L-R-D-A;
(SEQ ID NO: 82)
K-K-K-K-K-K-K-K-L-R-V-R-M-S-S-H-L-R-K-L-R-K-R-L-L-
R-D-A;
(SEQ ID NO: 83)
K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-M-S-S-H-L-R-K-L-R-
K-R-L-L-R-D-A;
(SEQ ID NO: 84)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-M-S-S-H-L-
R-K-L-R-K-R-L-L-R-D-A;
(SEQ ID NO: 85)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-M-
S-S-H-L-R-K-L-R-K-R-L-L-R-D-A;
(SEQ ID NO: 86)
K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-V-R-K-R-L-L-R-D-A;
(SEQ ID NO: 87)
K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-V-R-K-R-L-L-
R-D-A;
(SEQ ID NO: 88)
K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-V-R-
K-R-L-L-R-D-A;
(SEQ ID NO: 89)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-
R-N-V-R-K-R-L-L-R-D-A;
(SEQ ID NO: 90)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-
A-S-H-L-R-N-V-R-K-R-L-L-R-D-A;
(SEQ ID NO: 91)
K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-M-R-K-R-L-L-R-D-A;
(SEQ ID NO: 92)
K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-M-R-K-R-L-L-
R-D-A;
(SEQ ID NO: 93)
K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-M-R-
K-R-L-L-R-D-A;
(SEQ ID NO: 94)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-
R-N-M-R-K-R-L-L-R-D-A;
(SEQ ID NO: 95)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-
A-S-H-L-R-N-M-R-K-R-L-L-R-D-A;
(SEQ ID NO: 96)
K-K-K-K-L-R-A-R-M-A-S-H-L-R-K-L-R-K-R-L-L-R-D-A;
(SEQ ID NO: 97)
K-K-K-K-K-K-K-K-L-R-A-R-M-A-S-H-L-R-K-L-R-K-R-L-L-
R-D-A;
(SEQ ID NO: 98)
K-K-K-K-K-K-K-K-K-K-K-K-L-R-A-R-M-A-S-H-L-R-K-L-R-
K-R-L-L-R-D-A;
(SEQ ID NO: 99)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-A-R-M-A-S-H-L-
R-K-L-R-K-R-L-L-R-D-A;
(SEQ ID NO: 100)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-A-R-M-
A-S-H-L-R-K-L-R-K-R-L-L-R-D-A;
(SEQ ID NO: 101)
K-K-K-K-L-R-V-R-L-S-S-H-L-R-K-L-R-K-R-L-M-R-D-A;
(SEQ ID NO: 102)
K-K-K-K-K-K-K-K-L-R-V-R-L-S-S-H-L-R-K-L-R-K-R-L-M-
R-D-A;
(SEQ ID NO: 103)
K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-S-S-H-L-R-K-L-R-
K-R-L-M-R-D-A;
(SEQ ID NO: 104)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-S-S-H-L-
R-K-L-R-K-R-L-M-R-D-A;
(SEQ ID NO: 105)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-
S-S-H-L-R-K-L-R-K-R-L-M-R-D-A;
(SEQ ID NO: 106)
K-K-K-K-L-R-S-R-L-A-S-H-L-R-K-L-R-K-R-L-M-R-D-A;
(SEQ ID NO: 107)
K-K-K-K-K-K-K-K-L-R-S-R-L-A-S-H-L-R-K-L-R-K-R-L-M-
R-D-A;
(SEQ ID NO: 108)
K-K-K-K-K-K-K-K-K-K-K-K-L-R-S-R-L-A-S-H-L-R-K-L-R-
K-R-L-M-R-D-A;
(SEQ ID NO: 109)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-S-R-L-A-S-H-L-
R-K-L-R-K-R-L-M-R-D-A;
(SEQ ID NO: 110)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-S-R-L-
A-S-H-L-R-K-L-R-K-R-L-M-R-D-A;
(SEQ ID NO: 111)
K-K-K-K-L-R-V-R-L-S-S-H-L-P-K-L-R-K-R-L-L-R-D-A;
(SEQ ID NO: 112)
K-K-K-K-K-K-K-K-L-R-V-R-L-S-S-H-L-P-K-L-R-K-R-L-L-
R-D-A;
(SEQ ID NO: 113)
K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-S-S-H-L-P-K-L-R-
K-R-L-L-R-D-A;
(SEQ ID NO: 114)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-S-S-H-L-
P-K-L-R-K-R-L-L-R-D-A;
(SEQ ID NO: 115)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-
S-S-H-L-P-K-L-R-K-R-L-L-R-D-A;
(SEQ ID NO: 116)
K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-M-R-K-R-L-M-R-D-A;
(SEQ ID NO: 117)
K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-M-R-K-R-L-M-
R-D-A;
(SEQ ID NO: 118)
K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-K-M-R-
K-R-L-M-R-D-A;
(SEQ ID NO: 119)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-
R-K-M-R-K-R-L-M-R-D-A;
(SEQ ID NO: 120)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-
A-S-H-L-R-K-M-R-K-R-L-M-R-D-A;
(SEQ ID NO: 121)
K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-L-P-K-R-L-L-R-D-A;
(SEQ ID NO: 122)
K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-L-P-K-R-L-L-
R-D-A;
(SEQ ID NO: 123)
K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-R-N-L-P-
K-R-L-L-R-D-A;
(SEQ ID NO: 124)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-S-H-L-
R-N-L-P-K-R-L-L-R-D-A;
(SEQ ID NO: 125)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-
A-S-H-L-R-N-L-P-K-R-L-L-R-D-A;
(SEQ ID NO: 131)
K-K-K-K-L-R-L-R-L-A-S-H-L-R-K-L-R-K-R-L-L-R-D-L;
(SEQ ID NO: 132)
K-K-K-K-K-K-K-K-L-R-L-R-L-A-S-H-L-R-K-L-R-K-R-L-L-
R-D-L;
(SEQ ID NO: 133)
K-K-K-K-K-K-K-K-K-K-K-K-L-R-L-R-L-A-S-H-L-R-K-L-R-
K-R-L-L-R-D-L;
(SEQ ID NO: 134)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-L-R-L-A-S-H-L-
R-K-L-R-K-R-L-L-R-D-L;
(SEQ ID NO: 135)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-L-R-L-
A-S-H-L-R-K-L-R-K-R-L-L-R-D-L;
(SEQ ID NO: 136)
K-K-K-K-L-R-V-R-L-A-N-H-L-R-K-L-R-K-R-L-L-R-D-L;
(SEQ ID NO: 137)
K-K-K-K-K-K-K-K-L-R-V-R-L-A-N-H-L-R-K-L-R-K-R-L-L-
R-D-L;
(SEQ ID NO: 138)
K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-N-H-L-R-K-L-R-
K-R-L-L-R-D-L;
(SEQ ID NO: 139)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-A-N-H-L-
R-K-L-R-K-R-L-L-R-D-L;
or
(SEQ ID NO: 140)
K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-K-L-R-V-R-L-
A-N-H-L-R-K-L-R-K-R-L-L-R-D-L.
12 . A method of treating a brain disorder in a subject, the method comprising administering to the subject a complex, or a pharmaceutically acceptable salt thereof, comprising a nerve growth factor associated with a carrier peptide, wherein the carrier peptide comprises the sequence:
X n —[B] m
wherein:
X is a hydrophilic amino acid;
B is a blood-brain barrier agent;
n is an integer from 4 to 50; and
m is integer from 1 to 3.
13 . The method of claim 12 , wherein the brain disorder is chosen from: meningitis, epilepsy, multiple sclerosis, neuromyelitis optica, late-stage neurological trypanosomiasis, Parkinson's, progressive multifocal leukoencephalopathy, De Vivo disease, Alzheimer's disease, HIV Encephalitis, and cancer.Join the waitlist — get patent alerts
Track US2019322723A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.