title: Pharmacokinetic properties of tandem d-peptides designed for treatment of Alzheimer's disease.
abstract: Peptides are more and more considered for the development of drug candidates. However, they frequently exhibit severe disadvantages such as instability and unfavourable pharmacokinetic properties. Many peptides are rapidly cleared from the organism and oral bioavailabilities as well as in vivo half-lives often remain low. In contrast, some peptides consisting solely of d-enantiomeric amino acid residues were shown to combine promising therapeutic properties with high proteolytic stability and enhanced pharmacokinetic parameters. Recently, we have shown that D3 and RD2 have highly advantageous pharmacokinetic properties. Especially D3 has already proven promising properties suitable for treatment of Alzheimer's disease. Here, we analyse the pharmacokinetic profiles of D3D3 and RD2D3, which are head-to-tail tandem d-peptides built of D3 and its derivative RD2. Both D3D3 and RD2D3 show proteolytic stability in mouse plasma and organ homogenates for at least 24h and in murine and human liver microsomes for 4h. Notwithstanding their high affinity to plasma proteins, both peptides are taken up into the brain following i.v. as well as i.p. administration. Although both peptides contain identical d-amino acid residues, they are arranged in a different sequence order and the peptides show differences in pharmacokinetic properties. After i.p. administration RD2D3 exhibits lower plasma clearance and higher bioavailability than D3D3. We therefore concluded that the amino acid sequence of RD2 leads to more favourable pharmacokinetic properties within the tandem peptide, which underlines the importance of particular sequence motifs, even in short peptides, for the design of further therapeutic d-peptides.
authors.affiliation: Institute of Complex Systems, Structural Biochemistry, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany. Electronic address: l.hofmann@fz-juelich.de.
authors.forename: Leonie H E
authors.initials: LH
authors.lastname: Leithold
authors.affiliation: Institute of Complex Systems, Structural Biochemistry, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany. Electronic address: n.jiang@fz-juelich.de.
authors.forename: Nan
authors.initials: N
authors.lastname: Jiang
authors.affiliation: Institute of Complex Systems, Structural Biochemistry, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany. Electronic address: j.post@fz-juelich.de.
authors.forename: Julia
authors.initials: J
authors.lastname: Post
authors.affiliation: Institute of Neuroscience and Medicine, Medical Imaging Physics, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany. Electronic address: n.niemietz@fz-juelich.de.
authors.forename: Nicole
authors.initials: N
authors.lastname: Niemietz
authors.affiliation: Institute of Complex Systems, Structural Biochemistry, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany. Electronic address: e.schartmann@fz-juelich.de.
authors.forename: Elena
authors.initials: E
authors.lastname: Schartmann
authors.affiliation: Institute of Complex Systems, Structural Biochemistry, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany. Electronic address: t.ziehm@fz-juelich.de.
authors.forename: Tamar
authors.initials: T
authors.lastname: Ziehm
authors.affiliation: Institute of Complex Systems, Structural Biochemistry, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany. Electronic address: j.kutzsche@fz-juelich.de.
authors.forename: Janine
authors.initials: J
authors.lastname: Kutzsche
authors.affiliation: Institute of Neuroscience and Medicine, Medical Imaging Physics, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany; Department of Neurology, Universitätsklinikum der RWTH Aachen, 52074 Aachen, Germany. Electronic address: n.j.shah@fz-juelich.de.
authors.forename: N Jon
authors.initials: NJ
authors.lastname: Shah
authors.affiliation: Institute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany. Electronic address: joerg.breitkreutz@uni-duesseldorf.de.
authors.forename: Jörg
authors.initials: J
authors.lastname: Breitkreutz
authors.affiliation: Institute of Neuroscience and Medicine, Medical Imaging Physics, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany; Department of Nuclear Medicine, Universitätsklinikum der RWTH Aachen, 52074 Aachen, Germany. Electronic address: k.j.langen@fz-juelich.de.
authors.forename: Karl-Josef
authors.initials: KJ
authors.lastname: Langen
authors.affiliation: Institute of Neuroscience and Medicine, Medical Imaging Physics, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany. Electronic address: a.willuweit@fz-juelich.de.
authors.forename: Antje
authors.initials: A
authors.lastname: Willuweit
authors.affiliation: Institute of Complex Systems, Structural Biochemistry, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany; Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany. Electronic address: d.willbold@fz-juelich.de.
authors.forename: Dieter
authors.initials: D
authors.lastname: Willbold
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D013237:Stereoisomerism
chemical_list: D000596:Amino Acids; D001798:Blood Proteins; D010455:Peptides
keywords: Alzheimer's disease; Beta amyloid ligand; Pharmacokinetics; Therapy; d-enantiomeric peptide