Increasing blood-brain barrier permeability with permeabilizer peptides
AssigneeAlkermes, Inc.
InventorsJohn W. Kozarich, Gary F. Musso, Bernard Malfroy-Camine
Life of this patent
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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.
Claims4
A blood-brain barrier permeabilizing peptide having the amino acid sequence of H-arginine-proline-hydroxyproline-glycine-thienylalanine-serineproline-(4- Me-tyrosine).psi.(CH.sub.2 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.
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).psi.(CH.sub.2 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.
Dependencies are inferred from the claim text.