BRAIN-LOCALIZING POLYPEPTIDES COMPRISING A MULTIVALENT BINDING MOIETY AND IMPROVED METABOLIC STABILITY
Brain-localizing polypeptides carrying a reactive group for linking to a molecule that does not have brain-localizing activity were successfully produced by introducing at least two lysine residues into cyclized polypeptides having a brain-localizing motif sequence. These polypeptides have improved metabolic stability compared to conventional brain-localizing polypeptides, and can efficiently translocate desired molecules into the brain.
1 . A cyclized polypeptide comprising a multivalent binding moiety, which is a cyclized polypeptide comprising a brain-localizing motif sequence and at least two lysine residues.
2 . The cyclized polypeptide of claim 1 , comprising two adjacent lysine residues.
3 . The cyclized polypeptide of claim 1 , wherein metabolic stability is improved.
4 . The cyclized polypeptide of claim 1 , wherein a PET nuclide-labeled molecule is attached to the ε-amino group of lysine, and/or a ligand molecule of a brain receptor is attached to the ε-amino group of another lysine.
5 . A carrier molecule for brain localization comprising the cyclized polypeptide of claim 1 as an active ingredient.
6 . A brain-localizing pharmaceutical agent, wherein a pharmaceutical agent is attached to the ε-amino group of a lysine residue of the cyclized polypeptide of claim 1 .
7 . A reagent for PET examination, which comprises the cyclized polypeptide of claim 4 as an active ingredient.
8 . A kit for producing a brain-localizing pharmaceutical agent, comprising at least the following substances as components:
(a) the cyclized polypeptide of claim 1 ; and
(b) a pharmaceutical agent.
9 . A kit for PET examination, which comprises at least the following substances as components:
(a) a cyclized polypeptide of claim 1 ; and
(b) a molecule labeled with a PET nuclide.
10 . A method for producing a cyclized brain-localizing polypeptide comprising a multivalent binding moiety, which comprises the step of forming an amide bond between the two ends of a polypeptide comprising lysines at both ends and a brain-localizing motif sequence.
11 . A method for producing a brain-localizing polypeptide with improved metabolic stability, which comprises the step of forming an amide bond between the two ends of a polypeptide comprising lysines at both ends and a brain-localizing motif sequence.
12 . A method for producing a brain-localizing pharmaceutical agent, comprising the step of attaching the ε-amino group of a lysine of the cyclized polypeptide of claim 1 to a pharmaceutical agent.
13 . A method for producing a regent for PET examination, comprising the step of attaching the s-amino group of a lysine of the cyclized polypeptide of claim 1 to a molecule labeled with a PET nuclide.
14 . A method for producing a brain-localizing ligand molecule, comprising the step of attaching the ε-amino group of a lysine of the cyclized polypeptide of claim 1 to a ligand molecule for a brain receptor.
15 . A method for cyclizing a brain-localizing polypeptide in a state that carries a multivalent binding moiety, comprising the step of forming an amide bond between the two ends of a polypeptide comprising lysines at both ends and a brain-localizing motif sequence.
16 . A method of improving metabolic stability of a brain-localizing polypeptide, comprising the step of forming an amide bond between the two ends of a polypeptide comprising lysines at both ends and a brain-localizing motif sequence.