US2010061932A1PendingUtilityA1

Peptides useful as cell-penetrating peptides

Assignee: EVONIK ROEHM GMBHPriority: Dec 30, 2005Filed: Oct 25, 2006Published: Mar 11, 2010

Est. expiryDec 30, 2025(expired)· nominal 20-yr term from priority

Inventors:Roland Brock Rainer Fischer Mariola Fotin-Mleczek Hansjoerg Hufnagel Norbert Windhab

A61P 31/10A61P 35/00A61P 29/00A61P 21/00A61P 17/06A61P 19/02A61K 39/385A61K 2039/53C07K 14/79A61K 51/088A61K 47/644A61K 31/713C07K 14/47C07K 14/00

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References

Claims

Abstract

The present invention is related to a peptide having an amino acid sequence comprising at least 8 consecutive amino acids of the human lactoferrin protein or of the bovine lactoferrin protein, whereby the peptide is suitable to act as a cell-penetrating peptide.

Claims

exact text as granted — not AI-modified

1 . A peptide having an amino acid sequence comprising at least 8 consecutive amino acids of the human lactoferrin protein or of the bovine lactoferrin protein, whereby the peptide is suitable to act as a cell-penetrating peptide.

2 . The peptide according to claim 1 , whereby the peptide comprises at least four cationic amino acids.

3 . The peptide according to claim 1 , whereby the human lactoferrin protein has an amino acid sequence according to SEQ. ID. No. 1 and the bovine lactoferrin protein has an amino acid sequence according to SEQ. ID. No. 2.

4 . The peptide according to claim 1 , whereby the peptide comprises at least two Cys residues or analogs thereof.

5 . The peptide according to claim 4 , whereby the peptide comprises a disulfide bond created by two Cys residues or an analogous bond formed by the cysteine analogs.

6 . The peptide according to claim 1 , whereby the peptide comprises a moiety having an alpha-helical conformation of about 12 to 20 amino acids in length, and a moiety having a beta-sheet conformation of about 8 to 12 amino acids in length.

7 . The peptide according to claim 1 , whereby the peptide comprises from about 8 to about 60 amino acid residues.

8 . The peptide according to claim 7 , whereby the peptide comprises from about 20 to about 45 amino acid residues.

9 . The peptide according to claim 1 , whereby the peptide has an amino acid sequence corresponding to amino acid positions 20 to 64 of the amino acid sequence according to SEQ. ID. No.1.

10 . The peptide according to claim 1 , whereby the peptide has an amino acid sequence, whereby the N-terminal end of the peptide is an amino acid corresponding to amino acid positions 20 to 64 of the amino acid sequence according to SEQ. ID. No.1 or SEQ. ID. No. 2.

11 . The peptide according to claim 1 , whereby the peptide is selected from the group comprising
a peptide having the amino acid sequence KCFQWQRNMR K VRGPPVSCIKR (SEQ. ID. No.3), a peptide having the amino acid sequence CFQWQRNMR K VRGPPVSC (SEQ. ID. No.4), a peptide having the amino acid sequence FQWQRNMR K VRGPPVS (SEQ. ID. No.5), a peptide having the amino acid sequence FQWQRNMRKVR (SEQ. ID. No.6), a peptide having the amino acid sequence KCRRWQWRMKKLGAPSITCVRR (SEQ. ID No. 29), and a peptide having the amino acid sequence CRRWQWRMKKLGAPSITC (SEQ. ID No. 30), and derivatives thereof.

12 . The peptide according to claim 11 , whereby the peptide comprise a sequence according to SEQ. ID No. 3, SEQ. ID No. 4, SEQ. ID No. 29, SEQ. ID No. 30 or a derivative of said sequences with an sequence identity of at least 40%.

13 . The peptide according to claim 11 , whereby the peptide is a derivative of the peptides according to any of SEQ. ID. No. 2 to 5, whereby the methionine residues is replaced by an amino acid selected from the group comprising valine, isoleucine, norvaline, leucine and norleucine.

14 . The peptide according to claim 13 , whereby the peptide is a peptide having an amino acid sequence selected from the group comprising

(SEQ. ID. No. 7)

KCFQWQRNVRKVRGPPVSCIKR

(SEQ. ID. No. 8)

KCFQWQRNIRKVRGPPVSCIKR

(SEQ. ID. No. 9)

KCFQWQRNXRKVRGPPVSCIKR, whereby X is norvaline,

(SEQ. ID. No. 10)

KCFQWQRNLRKVRGPPVSCIKR,

(SEQ. ID. No. 28)

KCFQWQRNXRKVRGPPVSCIKR, whereby X is norleucine,

(SEQ. ID. No. 11)

CFQWQRNVRKVRGPPVSC,

(SEQ. ID. No. 12)

CFQWQRNIRKVRGPPVSC,

(SEQ. ID. No. 13)

CFQWQRNXRKVRGPPVSC, whereby X is norvaline,

(SEQ. ID. No. 14)

CFQWQRNLRKVRGPPVSC,

(SEQ. ID. No. 15)

CFQWQRNXRKVRGPPVSC, whereby X is norleucine,

(SEQ. ID. No. 16)

FQWQRNVRKVRGPPVS,

(SEQ. ID. No. 17)

FQWQRNIRKVRGPPVS,

(SEQ. ID. No. 18)

FQWQRNXRKVRGPPVS, whereby X is norvaline,

(SEQ. ID. No. 19)

FQWQRNLRKVRGPPVS,

(SEQ. ID. No. 20)

FQWQRNXRKVRGPPVS, whereby X is norleucine,

(SEQ. ID. No. 21)

FQWQRNVRKVR,

(SEQ. ID. No. 22)

FQWQRNIRKVR,

(SEQ. ID. No. 23)

FQWQRNXRKVR, whereby X is norvaline,

(SEQ. ID. No. 24)

FQWQRNLRKVR,

and

(SEQ. ID. No. 25)

FQWQRNXRKVR, whereby X is norleucine.

15 . The peptide according to claim 11 , whereby the derivatives have a linkage group selected from the group comprising thioethers, whereby the linkage group replaces the disulfide bond formed by these Cys residues.

16 . The peptide according to claim 1 , whereby the peptide is radioactively labelled, preferably by having incorporated a radioactively labelled amino acid, whereby the radioactively labelled amino acid is a tritium-labelled amino acid.

17 . The peptide according to claim 1 , whereby the peptide further comprises a moiety which is suitable for detection using a method for detection, whereby such moiety is selected from the group comprising fluorophores, radioactive tracers and haptens, whereby preferably the hapten is biotin.

18 . A complex comprising a peptide selected from the group comprising a peptide according to claim 1 , human lactoferrin and bovine lactoferrin, and a cargo molecule.

19 . The complex according to claim 18 , whereby the cargo molecule is covalently or non-covalently bound to the peptide.

20 . The complex according to claim 18 , whereby the cargo molecule is selected from the group comprising nucleic acids, amino acids, peptides, proteins, carbohydrates, lipids, and small molecules and mixtures of any of thereof.

21 . The complex according to claim 18 , whereby the cargo molecule is present as or part or a structure, whereby the structure is selected from the group comprising nanoparticles, microparticles, liposomes and micelles.

22 . The complex according to claim 20 , whereby the nucleic acid is a nucleic acid selected from the group comprising DNA molecules, RNA molecules, PNA molecules, siRNA molecules, antisense molecules, ribozymes, aptamers, spiegelmers and decoy molecules.

23 . The complex according to claim 20 , whereby the peptide is selected from the group comprising peptides for vaccination.

24 . The complex according to claim 20 , whereby the nucleic acid is a nucleic acid-based vaccine.

25 . The complex according to claim 20 , whereby the nano-particles and/or the micro-particles comprise or consist of a pharmaceutically active compound.

26 . A composition comprising at least a peptide selected from the group comprising a peptide according to claim 1 , human lactoferrin and bovine lactoferrin, and a cargo molecule.

27 . A composition comprising a complex according to claim 18 .

28 . A nucleic acid coding for a peptide according to claim 1 , preferably having a nucleic acid sequence according to SEQ. ID. No. 26 or SEQ. ID. No. 27.

29 . A composition comprising a nucleic acid according to claim 28 and a cargo molecule.

30 . The composition according to claim 29 , whereby the cargo molecule is a nucleic acid and more particularly a RNA suitable for vaccination.

31 . The composition according to claim 29 , whereby the cargo molecule is a nucleic acid coding for a peptide.

32 . The composition according to claim 31 , whereby the nucleic acid according to claim 28 is operably linked to the nucleic acid coding for a peptide.

33 . The composition according to claim 31 , whereby the nucleic acid according to claim 28 and the nucleic acid coding for a peptide are linked in-frame.

34 . The composition according to claim 31 , whereby the peptide is a pharmaceutically active agent.

35 . Use of a peptide according to claim 1 as a cell-penetrating peptide.

36 . The method of using human lactoferrin or a functional derivative thereof or of bovine lactoferrin or a functional derivative thereof as a cell-penetrating peptide.

37 . The method according to claim 36 , whereby the human lactoferrin has an amino acid sequence comprising amino acid positions 20 to 711 of the amino acid sequence according to SEQ. ID. No. 1 or functional derivative thereof and/or the bovine lactoferrin has an amino acid sequence comprising amino acid positions 20 to 708 of the amino acid sequence according to SEQ. ID. No. 2 or a functional derivative thereof.

38 . The method of using a peptide according to claim 1 as a transfection agent.

39 . The method of using a human lactoferrin or a functional derivative thereof or of bovine lactoferrin or a functional derivative thereof as a transfection agent.

40 . The method according to claim 39 , whereby the human lactoferrin has an amino acid sequence comprising amino acid positions 20 to 711 of the amino acid sequence according to SEQ. ID. No. 1 and/or the bovine lactoferrin has an amino acid sequence comprising amino acid positions 20 to 708 of the amino acid sequence according to SEQ. ID. No. 2 or a functional derivative thereof.

41 . The method of using a composition according to claim 26 for the manufacture of a medicament.

42 . The method according to claim 41 , whereby the cargo molecule is a pharmaceutically active agent.

43 . The method of using a composition according to claim 26 for the manufacture of a diagnostic agent.

44 . The method according to claim 43 , whereby the cargo molecule is a diagnostic marker.

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