Cell-penetrating peptides having a central hydrophobic domain

Patent metadata

Field	Value
Publication number	US-9302014-B2
Application number	US-201214240832-A
Country	US
Kind code	B2
Filing date	Aug 29, 2012
Priority date	Aug 30, 2011
Publication date	Apr 5, 2016
Grant date	Apr 5, 2016

Abstract

The present invention discloses cell penetrating peptides (CPP or membrane translocating peptide) and their conjugates with cargo molecules. The peptides are useful as drug delivery systems, particularly as delivery vehicles for nucleotide-based therapeutics, such as polynucleotides, oligonucleotides and peptide nucleic acids. A CPPs of the invention provides a balance between good cell entry efficiency and low toxicity and comprises three contiguous domains: the central one being hydrophobic and the flanking ones consisting of arginine and aminohexanoic acid or beta-alanine residues. The hydrophobic domain contains a sequence selected from YQFLI, YRFLI, IQFLI and IRFLI.

First claim

The invention claimed is:

1. A 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

wherein
the total number of residues in Domains 1-3 combined is no more than 40,
the number of R (Arginine) residues in Domains 1 and 3 combined is at least 5,
the number of X residues in Domains 1 and 3 combined is at least 1,
the number of B residues in Domains 1 and 3 combined is at least 2, wherein X=aminohexanoic acid and B=betaAlanine,
Domain 2 comprises a sequence that contains at least 3 of the amino acids Z 1 Z 2 FLI [SEQ ID NO:798], where Z 1 , is Y or I and Z 2 is Q or R, and
Domain 2 does not contain an N- to C-terminal contiguous primary sequence of ILFQY [SEQ ID NO:799], ILFQ [SEQ ID NO:800] or ILIQ [SEQ ID NO:801].

2. A 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:

[SEQ ID NO: 762]

RXRZ 3

where Z 3 is selected from one of:

[SEQ ID NO: 763]

RBRRXR

[SEQ ID NO: 764]

RBRRX

[SEQ ID NO: 765]

RBRX

[SEQ ID NO: 766]

RBRXR

[SEQ ID NO: 767]

BRX

[SEQ ID NO: 768]

BX

[SEQ ID NO: 769]

RBR

[SEQ ID NO: 770]

RB,

or

[SEQ ID NO: 771]

RBRR

(ii) Domain 2 comprises a sequence that contains at least 3 of the amino acids Z 1 Z 2 FLI [SEQ ID NO:798], where Z 1 , is Y or I and Z 2 is Q or R, and wherein Domain 2 does not contain an N- to C-terminal contiguous primary sequence of ILFQY [SEQ ID NO:799], ILFQ [SEQ ID NO:800] or ILIQ [SEQ ID NO:801],
(iii) Domain 3 comprises a sequence chosen from:

[SEQ ID NO: 772]

RXRBRXRB

[SEQ ID NO: 773]

XRBRXRB

[SEQ ID NO: 774]

RXRRBRB

[SEQ ID NO: 775]

BRXRB

[SEQ ID NO: 776]

XRRBRB

[SEQ ID NO: 777]

RRBRB

[SEQ ID NO: 778]

XRBRB

[SEQ ID NO: 779]

RBRXRB

[SEQ ID NO: 780]

RXRBRB,

or

[SEQ ID NO: 781]

BRBRB

wherein X=aminohexanoic acid, B=betaAlanine.

3. The peptide of claim 2 , wherein Domain 2 comprises an N- to C-terminal contiguous primary sequence chosen from YQFLI [SEQ ID NO:802], IQFLI [SEQ ID NO:803], YRFLI [SEQ ID NO:804], YRFRLI [SEQ ID NO:805], FQILY [SEQ ID NO:806], QFLI [SEQ ID NO:807], QFL [SEQ ID NO:808], or ILFRY [SEQ ID NO:811].

4. The peptide of claim 2 , wherein Domain 1 comprises or consists of a sequence chosen from:

[SEQ ID NO: 782]

RXRRBRRXR

[SEQ ID NO: 783]

RXRRBRRX

Assignees

• Gait Michael John
• Arzumanov Andrey Alexandrovich
• Saleh Amer F
• Wood Matthew J A
• Betts Corinne
• Koo Taeyoung
• Medical Res Council

Inventors

• Gait Michael John
• Arzumanov Andrey Alexandrovich
• Saleh Amer F
• Wood Matthew J A
• Betts Corinne
• Koo Taeyoung

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/06

  Antianaemics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title