US2014051646A1PendingUtilityA1
Cell penetrating peptides
Est. expiryJun 4, 2028(~1.9 yrs left)· nominal 20-yr term from priority
A61P 7/06A61P 9/00A61P 35/00A61P 25/14A61P 25/16A61P 3/00A61P 25/28A61P 17/00A61P 21/00A61K 31/7125C07K 14/001C07K 2319/10A61P 21/04A61K 47/64C07K 7/02A61K 47/48246
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Claims
Abstract
The present invention discloses cell penetrating peptides and conjugates of a cell penetrating peptide and a cargo molecule.
Claims
exact text as granted — not AI-modified1 . A method of treating, preventing or ameliorating a disease in a patient in need of such treatment, prevention or amelioration, the method comprising administering a peptide-cargo conjugate to the patient thereby treating, preventing or ameliorating the disease, wherein the peptide-cargo conjugate comprises a peptide chemically conjugated to a cargo molecule, the peptide having a primary sequence structure comprised of at least three domains, having the arrangement:
N-terminus [Domain 1]-[Domain 2]-[Domain 3] C-terminus in which: (i) Domain 1 comprises a sequence chosen from:
RXRRBRRXR
[SEQ ID NO: 81]
RBRRXRRBR, or
[SEQ ID NO: 82]
RXRRXR
[SEQ ID NO: 74]
(ii) Domain 2 comprises a sequence chosen from:
ILFQ, or
[SEQ ID NO: 86]
ILIQ
[SEQ ID NO: 202]
(iii) Domain 3 comprises a sequence chosen from:
RXRBRXR
[SEQ ID NO: 159]
RBRXRBR
[SEQ ID NO: 162]
RXRRXR
[SEQ ID NO: 161]
RXRXRXR
[SEQ ID NO: 160]
RXRBRX
[SEQ ID NO: 163]
MKWHK, or
[SEQ ID NO: 203]
WKWHK
[SEQ ID NO: 204]
wherein X=aminohexanoyl, B=betaAlanine,
and wherein the cargo molecule comprises an active agent capable of treating, preventing or ameliorating the disease.
2 . The method of claim 1 , wherein the cargo molecule is conjugated to the peptide at the C-terminus of the peptide.
3 . The method of claim 1 , wherein the cargo molecule is chosen from a nucleic acid, peptide nucleic acid (PNA), phosphorodiamidate morpholino oligonucleotide (PMO), locked nucleic acid (LNA), antisense oligonucleotide, short interfering RNA (siRNA), peptide, cyclic peptide, protein, or drug.
4 . The method of claim 1 , wherein the cargo molecule has a molecular weight less than 5,000 Da.
5 . The method of claim 1 , wherein the disease is caused by a splicing deficiency.
6 . The method of claim 5 , wherein the cargo molecule comprises an oligonucleotide, peptide nucleic acid (PNA), phosphorodiamidate morpholino oligonucleotide (PMO), or locked nucleic acid (LNA) capable of preventing or correcting the splicing defect and/or increasing the production of correctly spliced mRNA molecules.
7 . The method of claim 1 , wherein the disease is chosen from Duchenne Muscular Dystrophy (DMD), Menkes Disease, β-thalassemia, frontotemporal dementia, parkinsonism, spinal muscular atrophy, Hutchinson-Gilford Progeria Syndrome, Ataxiatelangiectasia mutated (ATM), or cancer.
8 . The method of claim 1 , wherein the cargo molecule is PNADMD [SEQ ID NO:115] or PMODMD [SEQ ID NO:206] or a molecule having at least 90% sequence identity to one of PNADMD [SEQ ID NO:115] or PMODMD [SEQ ID NO:206].
9 . The method of claim 1 , wherein the disease is Duchenne Muscular Dystrophy (DMD) and the cargo molecule is PNADMD [SEQ ID NO:115] or PMODMD [SEQ ID NO:206] or a molecule having at least 90% sequence identity to one of PNADMD [SEQ ID NO:115] or PMODMD [SEQ ID NO:206].
10 . The method of claim 1 , wherein Domain 2 comprises a sequence chosen from ILFQY [SEQ ID NO:88], or ILIQY [SEQ ID NO:296].
11 . The method of claim 1 , wherein Domain 2 comprises a sequence chosen from:
Z 2 Z 3 ILFQZ 4 , or
[SEQ ID NO: 89]
Z 2 Z 3 ILIQZ 4
[SEQ ID NO: 297]
wherein Z 2 =I or no amino acid, Z 3 =K, dK, H, R or no amino acid, Z 4 =N or Y.
12 . The method of claim 1 , wherein Domain 3 comprises a sequence chosen from:
Z 7 Z 8 MKWHK, or
[SEQ ID NO: 298]
Z 7 Z 8 WKWHK
[SEQ ID NO: 299]
where Z 7 =R, dR, K or dK (wherein d=D-aminoacid)
Z 8 =R, H or K.
13 . The method of claim 1 , wherein Domain 3 comprises a sequence chosen from:
dRRMKWHK
[SEQ ID NO: 111]
dRHMKWHK
[SEQ ID NO: 155]
dRRWKWHK
[SEQ ID NO: 157]
dKRMKWHK, or
[SEQ ID NO: 156]
dKHWKWHK.
[SEQ ID NO: 158]
14 . The method of claim 1 , wherein Domain 1 comprises a sequence chosen from:
(RXR) n where n = 2, 3 or 4, or
[SEQ ID NOs: 74-76]
RXRRXRIdR.
[SEQ ID NO: 80]
15 . The method of claim 1 , wherein the peptide has a maximum length of 30 residues, including natural amino acids, X and B residues.
16 . The method of claim 1 , wherein Domain 1 has a length of from 6 to 11 residues, Domain 2 has a length of from 4 to 9 residues, and Domain 3 has a length of from 4 to 15 residues, wherein the lengths include natural amino acids, X and B residues.
17 . The method of claim 1 , wherein the peptide comprises, or consists of, a sequence chosen from one of SEQ ID NOs:242-295 ( FIG. 25 ) or a sequence having at least 90% sequence identity to one of SEQ ID NOs:242-295 ( FIG. 25 ).
18 . The method of claim 1 , wherein the peptide comprises, or consists of, the sequence of Domains 1 to 3 or Domains 1 to 4 of one of Pip-5e, Pip-5j or Pip-5l (SEQ ID NOs:230, 234 or 236) or a sequence having at least 90% sequence Identity to the sequence of Domains 1 to 3 or Domains 1 to 4 of one of Pip-5e, Pip-5j or Pip-5l (SEQ ID NOs:230, 234 or 236).
19 . The method of claim 1 , wherein the peptide comprises, or consists of, a sequence chosen from one of:
Z 1 Z 2 Z 3 ILFQZ 4 Z 5 RMKWHK
[SEQ ID NO: 113]
Z 1 Z 2 Z 3 ILFQZ 4 Z 5 HMKWHK
[SEQ ID NO: 183]
Z 1 Z 2 Z 3 ILFQZ 4 Z 5 RWKWHK
[SEQ ID NO: 184]
Z 1 Z 2 Z 3 ILFQZ 4 Z 5 HWKWHK
[SEQ ID NO: 185]
Z 1 Z 2 Z 3 ILFQZ 4 RXRBRXR
[SEQ ID NO: 186]
Z 1 Z 2 Z 3 ILFQZ 4 RXRXRXR
[SEQ ID NO: 187]
Z 1 Z 2 Z 3 ILFQZ 4 RXRRXR
[SEQ ID NO: 188]
Z 1 Z 2 Z 3 ILFQZ 4 RBRXRBR
[SEQ ID NO: 189]
Z 1 Z 2 Z 3 ILFQZ 4 RXRBRXR
[SEQ ID NO: 190]
Z 1 Z 2 Z 3 ILFQZ 4 RXRBRX
[SEQ ID NO: 191]
Z 1 Z 2 Z 3 ILIQZ 4 Z 5 RMKWHK
[SEQ ID NO: 192]
Z 1 Z 2 Z 3 ILIQZ 4 Z 5 HMKWHK
[SEQ ID NO: 193]
Z 1 Z 2 Z 3 ILIQZ 4 Z 5 RWKWHK
[SEQ ID NO: 194]
Z 1 Z 2 Z 3 ILIQZ 4 Z 5 HWKWHK
[SEQ ID NO: 195]
Z 1 Z 2 Z 3 ILIQZ 4 RXRBRXR
[SEQ ID NO: 196]
Z 1 Z 2 Z 3 ILIQZ 4 RXRXRXR
[SEQ ID NO: 197]
Z 1 Z 2 Z 3 ILIQZ 4 RXRRXR
[SEQ ID NO: 198]
Z 1 Z 2 Z 3 ILIQZ 4 RBRXRBR
[SEQ ID NO: 199]
Z 1 Z 2 Z 3 ILIQZ 4 RXRBRXR
[SEQ ID NO: 200]
Z 1 Z 2 Z 3 ILIQZ 4 RXRBRX
[SEQ ID NO: 201]
wherein:
Z 1 =(RXFR) n where n=2, 3, or 4; (RBR), where n=2, 3, or 4; (R), where m=5, 6, 7 or 8; RXRRXRIdR [SEQ ID NO:80]; RXRRBRRXR [SEQ ID NO:81]; or RBRRXRRBR SEQ ID NO:82;
Z 2 =I or no amino acid
Z 3 =K, dK, H, R or no amino acid
Z 4 =N, Y
Z 5 =R or dR. K or dK
wherein d=D-aminoacid.
20 . The method of claim 1 , wherein the peptide comprises, or consists of, a sequence chosen from one of SEQ ID NOs:34-73 ( FIG. 16 ), or a sequence having at least 90% sequence identity to one of SEQ ID NOs:34-73 ( FIG. 16 ).
21 . The method of claim 1 , wherein the peptide further comprises a linker sequence at the C-terminus.
22 . The method of claim 21 , wherein the linker sequence is chosen from BCys, XCys, Cys, GGCys, BBCys, BXCys, XBCys, BX, or XB.Cited by (0)
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