Description: Metabolic resistance of the D-peptide RD2 developed for direct elimination of amyloid-β oligomers

This title appears in the Scientific Report : 2019

Metabolic resistance of the D-peptide RD2 developed for direct elimination of amyloid-β oligomers

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 co...

Personal Name(s):	Elfgen, Anne
	Hupert, Michelle / Bochinsky, Kevin / Tusche, Markus / González de San Román Martin, Estibaliz / Gering, Ian / Sacchi, Silvia / Pollegioni, Loredano / Huesgen, Pitter F. / Hartmann, Rudolf / Santiago-Schübel, Beatrix / Kutzsche, Janine (Corresponding author) / Willbold, Dieter (Corresponding author)
Contributing Institute:	Analytik; ZEA-3 Strukturbiochemie; ICS-6
Published in:	Scientific reports, 9 (2019) 1, S. 5715
Imprint:	[London] Macmillan Publishers Limited, part of Springer Nature 2019
PubMed ID:	30952881
DOI:	10.1038/s41598-019-41993-6
Document Type:	Journal Article
Research Program:	Physical Basis of Diseases
Link:	Get full text Get full text OpenAccess OpenAccess
	Publikationsportal JuSER

Please use the identifier: http://hdl.handle.net/2128/22182 in citations.
Please use the identifier: http://dx.doi.org/10.1038/s41598-019-41993-6 in citations.

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.