TY  - JOUR
AU  - Elfgen, Anne
AU  - Hupert, Michelle
AU  - Bochinsky, Kevin
AU  - Tusche, Markus
AU  - González de San Román Martin, Estibaliz
AU  - Gering, Ian
AU  - Sacchi, Silvia
AU  - Pollegioni, Loredano
AU  - Huesgen, Pitter F.
AU  - Hartmann, Rudolf
AU  - Santiago-Schübel, Beatrix
AU  - Kutzsche, Janine
AU  - Willbold, Dieter
TI  - Metabolic resistance of the D-peptide RD2 developed for direct elimination of amyloid-β oligomers
JO  - Scientific reports
VL  - 9
IS  - 1
SN  - 2045-2322
CY  - [London]
PB  - Macmillan Publishers Limited, part of Springer Nature
M1  - FZJ-2019-02988
SP  - 5715
PY  - 2019
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:30952881
UR  - <Go to ISI:>//WOS:000463482800054
DO  - DOI:10.1038/s41598-019-41993-6
UR  - https://juser.fz-juelich.de/record/862746
ER  -