Journal Article

FZJ-2019-02988

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Metabolic resistance of the D-peptide RD2 developed for direct elimination of amyloid-β oligomers

Elfgen, A.FZJ* ; Hupert, M.FZJ* ; Bochinsky, K.FZJ* ; Tusche, M.FZJ* ; González de San Román Martin, E. ; Gering, I.FZJ* ; Sacchi, S. ; Pollegioni, L. ; Huesgen, P. F.FZJ* ; Hartmann, R.FZJ* ; Santiago-Schübel, B.FZJ* ; Kutzsche, J. (Corresponding author)FZJ* ; Willbold, D. (Corresponding author)FZJ*

2019
Macmillan Publishers Limited, part of Springer Nature [London]

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Please use a persistent id in citations: http://hdl.handle.net/2128/22182  doi:10.1038/s41598-019-41993-6

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder leading to dementia. Aggregation of the amyloid-β peptide (Aβ) plays an important role in the disease, with Aβ oligomers representing the most toxic species. Previously, we have developed the Aβ oligomer eliminating therapeutic compound RD2 consisting solely of D-enantiomeric amino acid residues. RD2 has been described to have an oral bioavailability of more than 75% and to improve cognition in transgenic Alzheimer’s disease mouse models after oral administration. In the present study, we further examined the stability of RD2 in simulated gastrointestinal fluids, blood plasma and liver microsomes. In addition, we have examined whether RD2 is a substrate for the human D-amino acid oxidase (hDAAO). Furthermore, metabolite profiles of RD2 incubated in human, rodent and non-rodent liver microsomes were compared across species to search for human-specific metabolites that might possibly constitute a threat when applying the compound in humans. RD2 was remarkably resistant against metabolization in all investigated media and not converted by hDAAO. Moreover, RD2 did not influence the activity of any of the tested enzymes. In conclusion, the high stability and the absence of relevant human-specific metabolites support RD2 to be safe for oral administration in humans.

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Contributing Institute(s):

1. Strukturbiochemie (ICS-6)
2. Analytik (ZEA-3)

Research Program(s):

1. 553 - Physical Basis of Diseases (POF3-553) (POF3-553)

Appears in the scientific report 2019

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