US2019337988A1PendingUtilityA1
Novel transporter constructs and transporter cargo conjugate molecules
Est. expiryDec 22, 2028(~2.4 yrs left)· nominal 20-yr term from priority
Inventors:Christophe Bonny
A61P 9/00A61P 37/04A61P 3/10A61P 37/06A61P 43/00A61P 37/00A61P 31/14A61P 25/28A61P 25/24A61P 35/02A61P 27/16A61P 35/00A61P 31/22A61P 25/00A61P 31/20A61P 31/18A61P 29/00A61P 31/00A61P 31/12A61P 1/00A61P 1/16A61P 15/08A61P 17/14A61P 19/00A61P 1/04A61P 15/00A61K 47/64C07K 14/005A61K 47/645C12N 2740/16322A61K 38/00Y02A50/385Y02A50/463Y02A50/30
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Claims
Abstract
The present invention relates to novel transporter constructs of the generic formula (I) DlLLLxDm(LLLyDn)a and variants thereof. The present invention also refers to transporter cargo conjugate molecules, particularly of conjugates of the novel transporter constructs with a cargo moiety, e.g. proteins or peptides, nucleic acids, cytotoxic agents, organic molecules, etc. The present invention furthermore discloses (pharmaceutical) compositions comprising these conjugates and methods of treatment and uses involving such transporter constructs.
Claims
exact text as granted — not AI-modified1 . A transport cargo conjugate molecule comprising
a) a component (A) comprising a transporter construct comprising a sequence selected from the group consisting of an amino acid sequence comprising rKKRrQRRr (SEQ ID NO:20) and an amino acid sequence comprising rRRQrRKKr (SEQ ID NO:21), wherein lowercase designations indicate D-amino acids and uppercase designations indicate L-amino acids; and b) a component (B) comprising an effector molecule.
2 . The transporter cargo conjugate molecule of claim 1 , wherein the sequence is conjugated with a trafficking sequence selected from the group consisting of:
a sequence derived from HIV-I TAT protein (SEQ ID NO: 8), a sequence derived from an amino acid sequence containing TAT residues 48-57 or 48 to 57 of HIV-I TAT protein (SEQ ID NO: 8), a sequence derived from HSV VP22, obtained from Herpes simplex, a sequence derived from antennapedia carrier sequence, obtained from Drosophila antennapedia, FGF, lactoferrin, and a sequence derived from a basic peptide having a length of 5 to 15 amino acids, or 10 to 12 amino acids and comprising at least 80%, or 85% or 90% basic amino acids selected from arginine, lysine and histidine, or is selected from the group consisting of: arginine rich peptide sequences, HSV VP22, PTD-4 derived proteins or peptides, RGD-K 16 , PEPT1, PEPT2, or proteins or peptides derived from PEPT1 or PEPT2, SynB3 or SynB3 derived proteins or peptides, protein convertase (PC) inhibitors, P21 derived proteins or peptides, and JNK1 derived proteins or peptides.
3 . The transporter cargo conjugate molecule of claim 1 , wherein the sequence is conjugated with one of the following sequences or a reverse sequence thereof,
SEQUENCE/
SEQ
PEPTIDE NAME
ID
AA
SEQUENCE
TAT (1-86)
8
86
MEPVDPRLEP WKHPGSQPKT
ACTNCYCKKC CFHCQVCFIT
KALGISYGRK KRRQRRRPPQ
GSQTHQVSLS KQPTSQSRGD
PTGPKE
TAT (37-72)
9
36
CFITKALGIS YGRKKRRQRR
RPPQGSQTHQ VSLSKQ
TAT (37-58)
10
22
CFITKALGIS YGRKKRRQRR
RP
TAT (38-58)GGC
11
24
FITKALGISY GRKKRRQRRR
PGGC
TAT CGG(47-58)
12
15
CGGYGRKKRR QRRRP
TAT (47-58)GGC
13
15
YGRKKRRQRR RPGGC
TAT (1-72) Mut
14
56
MEPVDPRLEP WKHPGSQPKT
Cys/Ala 72
AFITKALGIS YGRKKRRQRR
RPPQGSQTHQ VSLSKQ
L-TAT (sla)
17
10
GRKKRRQRRR
L-TAT (slb)
18
9
RKKRRQRRR
L-TAT (slc)
19
11
YDRKKRRQRRR
r 3 -L-TAT
20
9
rKKRrQRRr
r 3 -L-TATi
21
9
rRRQrRKKr
βA-r 3 -L-TAT
22
10
βA-rKKRrQRRr
βA-r 3 -L-TATi
23
10
βA-rRRQrRKKr
FITC-βA-r 3 -L-TAT
24
10
FITC-βA-rKKRrQRRr
FITC-βA-r 3 -L-TATi
25
10
FITC-βA-rRRQrRKKr
TAT(s2-1)
26
9
rAKRrQRRr
TAT(s2-2)
27
9
rKARrQRRr
TAT(s2-3)
28
9
rKKArQRRr
TAT(s2-4)
29
9
rKKRrARRr
TAT(s2-5)
30
9
rKKRrQARr
TAT(s2-6)
31
9
rKKRrQRAr
TAT(s2-7)
32
9
rDKRrQRRr
TAT(s2-8)
33
9
rKDRrQRRr
TAT(s2-9)
34
9
rKKDrQRRr
TAT(s2-10)
35
9
rKKRrDRRr
TAT(s2-11)
36
9
rKKRrQDRr
TAT(s2-12)
37
9
rKKRrQRDr
TAT(s2-13)
38
9
rEKRrQRRr
TAT(s2-14)
39
9
rKERrQRRr
TAT(s2-15)
40
9
rKKErQRRr
TAT(s2-16)
41
9
rKKRrERRr
TAT(s2-17)
42
9
rKKRrQERr
TAT(s2-18)
43
9
rKKRrQREr
TAT(s2-19)
44
9
rFKRrQRRr
TAT(s2-20)
45
9
rKFRrQRRr
TAT(s2-21)
46
9
rKKFrQRRr
TAT(s2-22)
47
9
rKKRrFRRr
TAT(s2-23)
48
9
rKKRrQFRr
TAT(s2-24)
49
9
rKKRrQRFr
TAT(s2-25)
50
9
rRKRrQRRr
TAT(s2-26)
51
9
rKRRrQRRr
TAT(s2-27)
52
9
rKKKrQRRr
TAT(s2-28)
53
9
rKKRrRRRr
TAT(s2-29)
54
9
rKKRrQKRr
TAT(s2-30)
55
9
rKKRrQRKr
TAT(s2-31)
56
9
rHKRrQRRr
TAT(s2-32)
57
9
rKHRrQRRr
TAT(s2-33)
58
9
rKKHrQRRr
TAT(s2-34)
59
9
rKKRrHRRr
TAT(s2-35)
60
9
rKKRrQHRr
TAT(s2-36)
61
9
rKKRrQRHr
TAT(s2-37)
62
9
rIKRrQRRr
TAT(s2-38)
63
9
rKIRrQRRr
TAT(s2-39)
64
9
rKKIrQRRr
TAT(s2-40)
65
9
rKKRrIRRr
TAT(s2-41)
66
9
rKKRrQIRr
TAT(s2-42)
67
9
rKKRrQRIr
TAT(s2-43)
68
9
rLKRrQRRr
TAT(s2-44)
69
9
rKLRrQRRr
TAT(s2-45)
70
9
rKKLrQRRr
TAT(s2-46)
71
9
rKKRrLRRr
TAT(s2-47)
72
9
rKKRrQLRr
TAT(s2-48)
73
9
rKKRrQRLr
TAT(s2-49)
74
9
rMKRrQRRr
TAT(s2-50)
75
9
rKMRrQRRr
TAT(s2-51)
76
9
rKKMrQRRr
TAT(s2-52)
77
9
rKKRrMRRr
TAT(s2-53)
78
9
rKKRrQMRr
TAT(s2-54)
79
9
rKKRrQRMr
TAT(s2-55)
80
9
rNKRrQRRr
TAT(s2-56)
81
9
rKNRrQRRr
TAT(s2-57)
82
9
rKKNrQRRr
TAT(s2-58)
83
9
rKKRrNRRr
TAT(s2-59)
84
9
rKKRrQNRr
TAT(s2-60)
85
9
rKKRrQRNr
TAT(s2-61)
86
9
rQKRrQRRr
TAT(s2-62)
87
9
rKQRrQRRr
TAT(s2-63)
88
9
rKKQrQRRr
TAT(s2-64)
89
9
rKKRrKRRr
TAT(s2-65)
90
9
rKKRrQQRr
TAT(s2-66)
91
9
rKKRrQRQr
TAT(s2-67)
92
9
rSKRrQRRr
TAT(s2-68)
93
9
rKSRrQRRr
TAT(s2-69)
94
9
rKKSrQRRr
TAT(s2-70)
95
9
rKKRrSRRr
TAT(s2-71)
96
9
rKKRrQSRr
TAT(s2-72)
97
9
rKKRrQRSr
TAT(s2-73)
98
9
rTKRrQRRr
TAT(s2-74)
99
9
rKTRrQRRr
TAT(s2-75)
100
9
rKKTrQRRr
TAT(s2-76)
101
9
rKKRrTRRr
TAT(s2-77)
102
9
rKKRrQTRr
TAT(s2-78)
103
9
rKKRrQRTr
TAT(s2-79)
104
9
rVKRrQRRr
TAT(s2-80)
105
9
rKVRrQRRr
TAT(s2-81)
106
9
rKKVrQRRr
TAT(s2-82)
107
9
rKKRrVRRr
TAT(s2-83)
108
9
rKKRrQVRr
TAT(s2-84)
109
9
rKKRrQRVr
TAT(s2-85)
110
9
rWKRrQRRr
TAT(s2-86)
111
9
rKWRrQRRr
TAT(s2-87)
112
9
rKKWrQRRr
TAT(s2-88)
113
9
rKKRrWRRr
TAT(s2-89)
114
9
rKKRrQWRr
TAT(s2-90)
115
9
rKKRrQRWr
TAT(s2-91)
116
9
rYKRrQRRr
TAT(s2-92)
117
9
rKYRrQRRr
TAT(s2-93)
118
9
rKKYrQRRr
TAT(s2-94)
119
9
rKKRrYRRr
TAT(s2-95)
120
9
rKKRrQYRr
TAT(s2-96)
121
9
rKKRrQRYr
r 3 R 6
122
9
rRRRrRRRr
L-R 9
123
9
RRRRRRRRR
L-R 8
124
8
RRRRRRRR
L-R 7
125
7
RRRRRRR
L-R 6
126
6
RRRRRR
L-R 5
127
5
RRRRR
PTD-4
128
11
YARAAARQARA
PTD-4 (variant 1)
129
11
WARAAARQARA
PTD-4 (variant 2)
130
11
WARAQRAAARA
L-P1 Penetratin
131
16
RQVKVWFQNRRMKWKK
D-P1 Penetratin
132
16
KKWKMRRNQFWVKVQR
JNKI, bestfit
133
17
WKRAAARKARAMSLNLF
JNKI, bestfit
134
17
WKRAAARAARAMSLNLF
(variant 1)
MDCK transcytose
135
9
RYRGDLGRR
sequence
YKGL
136
4
YKGL
wherein lowercase designations indicate D-amino acids and uppercase designations indicate L-amino acids and FITC is fluorescein isothiocyanate.
4 . The transporter cargo conjugate molecule of claim 2 , wherein the arginine rich peptide sequence comprises 5, 6, 7, 8, or 9 arginines.
5 . The transporter cargo conjugate molecule of claim 2 , wherein the sequence is conjugated to a trafficking sequence derived from HIV-1 TAT protein having a Tyrosine (Y) at position 2 of the TAT derived sequence.
6 . The transporter cargo conjugate molecule of claim 5 , wherein the trafficking sequence derived from HIV-1 TAT protein having a Tyrosine (Y) at position 2 of the TAT derived sequence is TAT(s2-91) (SEQ ID NO: 116).
7 . The transporter cargo conjugate molecule of claim 2 , wherein the sequence is conjugated to any of the trafficking sequences listed having at least 80% or 85%, or at least 90%, or at least 95%, or at least 99% sequence homology over the whole length of any of the trafficking sequences of claim 2 .
8 . The transporter cargo conjugate molecule of claim 1 , wherein the effector molecule is selected from the group consisting of therapeutically active proteins and peptides, protein kinase inhibitors, inhibitors of protein kinase c-Jun amino terminal kinase, antigens, antibodies, apoptotic factors, proteases implicated in pathological states, peptidic protease inhibitors, BH3-domains or BH3-only proteins, nucleic acids encoding these proteins, siRNA, antisense RNAs, cytotoxic agents, and small organic compounds.
9 . The transporter cargo conjugate molecule of claim 1 further comprising at least one additional component (C), (D) and/or (E) different to component (B), wherein the at least one optional additional component (C), (D) and/or (E) is selected independently from each other from different effector molecules or their fragments or variants as defined for component (B).
10 . The transporter cargo conjugate molecule of claim 9 , wherein components (A) and (B), and optionally (C), (D) and/or (E) are covalently linked with each other.
11 . The transporter cargo conjugate molecule of claim 10 , wherein the at least one additional component (C), (D) and/or (E) is selected from a signal sequence or localization sequence, which directs the inventive transporter cargo conjugate molecule to a particular intracellular target localization or to a particular cell type.
12 . The transporter cargo conjugate molecule of claim 11 , wherein component (B) and/or the at least one additional component (C), (D) and/or (E) is (are) a protein or peptide sequence and is (are) composed of L-amino acids, D-amino acids or a mixture of both.
13 . The transporter cargo conjugate molecule of claim 12 , wherein component (A) is positioned at the C-terminal end of the transporter cargo conjugate molecule, provided that component (B) is a protein or peptide sequence.
14 . A pharmaceutical composition comprising a transporter cargo conjugate molecule of claim 1 and optionally a pharmaceutically acceptable carrier and/or vehicle.
15 . A method of prophylaxis, treatment and/or amelioration of a disease, the method comprising administering to a patient in need thereof a transporter cargo conjugate molecule of claim 1 , wherein the disease is selected from the group consisting of cancer or tumor diseases, diseases caused by defective apoptosis, inflammatory diseases, infectious diseases, viral (infectious) diseases, diseases strongly related to JNK signaling, autoimmune disorders or diseases, cardiovascular diseases, neuronal or neurodegenerative diseases, diseases of the liver, diseases of the spine, diseases of the uterus, major depressive disorders, non-chronic or chronic inflammatory digestive diseases, hearing loss, diseases of the inner ear.Cited by (0)
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