Increasing blood-brain barrier permeability with permeabilizer peptides

• US 5,506,206 A
• Filed: 09/13/1993
• Issued: 04/09/1996
• Est. Priority Date: 04/23/1990
• Status: Expired due to Term

• Current Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Original Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Inventors: Musso, Gary F., Malfroy-Camine, Bernard, Kozarich, John W.
• Primary Examiner(s): Chan, Christina Y.
• Assistant Examiner(s): Prickril, Benet
• Application Number:
  US08/121,058
• Time in Patent Office: 939 Days
• Field of Search: 514/15, 530/314, 530/328
• US Class Current: 514/1.2
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/043 Kallidins; Bradykinins; Related peptides
• CPC Class Codes: A61K 38/08 Peptides having 5 to 11 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 47/42 Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein oligopeptides having up to five amino acids A61K47/183; polyamino acids A61K47/34
• CPC Class Codes: C07K 7/02 Linear peptides containing at least one abnormal peptide link
• CPC Class Codes: C07K 7/18 Kallidins; Bradykinins; Related peptides

Abstract

Polypeptides called receptor mediated permeabilizers (RMP) increase the permeability of the blood-brain barrier to molecules such as therapeutic agents or diagnostic agents. These receptor mediated permeabilizers are more efficacious than bradykinin in causing the blood-brain barrier to become more permeable. The permeabilizer A-7 or conformational analogues can be intravenously co-administered to a host together with molecules whose desired destination is the cerebrospinal fluid compartment of the brain. The permeabilizer A-7 or conformational analogues allow these molecules to penetrate the blood-brain barrier and arrive at this destination.

Claims

1. A blood-brain barrier permeabilizing peptide having the amino acid sequence of H-arginine-proline-hydroxyproline-glycine-thienylalanine-serineproline-(4-Me-tyrosine)ψ

(CH₂ NH)-arginine-OH (SEQ ID NO;

     1) or a conformational analogue thereof which is said peptide with at least one of the following modifications;

a) the N-terminal arginine is replaced by an amino acid analogue containing a guanidino side chain;

b) the second amino acid (proline) is replaced by hydroxyproline, dehydroproline or N-methylalanine;

c) the third amino acid (hydroxyproline) is replaced by proline, dehydroproline, alanine or N-methylalanine;

d) the fifth amino acid (thienylalanine) is replaced by another aromatic amino acid or a hydrophobic aliphatic amino acid;

e) the sixth amino acid (serine) is replaced by glycine or alanine;

f) the seventh amino acid (proline) is replaced by hydroxyproline, dehydroproline or N-methylalanine; and

g) the C-terminal arginine is replaced by an amino acid analogue containing a guanidino side chain

the C-terminal arginine is replaced by an amino acid analogue containing a guanidino side chain; and

b. a pharmaceutically acceptable carrier.

3. The blood-brain barrier permeabilizing peptide of claim 1 wherein said modification is chosen from:

a) β

-cycloarginine, homoarginine, γ

-hydroxyarginine, canavanine, N.sup.ω

-amidinocitrulline, 2-amino-4-guanidobutanoic acid for the N-terminal or C-terminal arginine;

b) hydroxyproline or dehydroproline for the second or seventh amino acids (proline);

c) proline or dehydroproline for the third amino acid (hydroxyproline);

d) dehydrophenylalanine, phenylalanine or another aromatic analogue for the fifth amino acid (thienylalanine); and

e) glycine for the sixth amino acid (serine).

4. The blood-brain barrier permeabilizing peptide of claim 1 wherein all optically active amino acids are of the L-configuration.

2. A pharmaceutical composition for administration to an animal to increase the permeability of the blood-brain barrier to a molecule, comprising:

a) an effective amount of a peptide with the amino acid sequence of H-arginine-proline-hydroxyproline-glycine-thienylalanine-serine-proline-4--Me-tyrosine)ψ

(CH₂ NH)-arginine-OH (SEQ ID NO;

     1) or a conformational analogue thereof which is said peptide with at least one of the following modifications;

i) the N-terminal arginine is replaced by an amino acid analogue containing a guanidino side chain;

ii) the second amino acid (proline) is replaced by hydroxyproline, dehydroproline or N-methylalanine;

iii) the third amino acid (hydroxyproline) is replaced by proline, dehydroproline, alanine or N-methylalanine;

iv) the fifth amino acid (thienylalanine) is replaced by another aromatic amino acid or a hydrophobic aliphatic amino acid;

v) the sixth amino acid (serine) is replaced by glycine or alanine;

vi) the seventh amino acid (proline) is replaced by hydroxyproline, dehydroproline or N-methylalanine; and

vii) the eighth amino acid (4-Me-tyrosine) is replaced by another O-alkyl tyrosine or a hydrophobic aliphatic amino acid.