Description: Oral absorption enhancement of the amyloid-β oligomer eliminating compound RD2 by conjugation with folic acid

This title appears in the Scientific Report : 2021

Oral absorption enhancement of the amyloid-β oligomer eliminating compound RD2 by conjugation with folic acid

Amyloid-β (Aβ) plays a central role in the development and progression of Alzheimer's disease (AD) with Aβ oligomers representing the most toxic species. The all-d-enantiomeric peptide RD2, which recently successfully completed clinical phase I, specifically eliminates Aβ oligomers in vitro as...

Personal Name(s):	Elfgen, Anne
	Santiago-Schübel, Beatrix / Hupert, Michelle / Schemmert, Sarah / Schartmann, Elena / Tusche, Markus / Gering, Ian / Zafiu, Christian / Kutzsche, Janine (Corresponding author)
Contributing Institute:	Analytik; ZEA-3 Strukturbiochemie; IBI-7
Published in:	European journal of pharmaceutical sciences, 156 (2021) S. 105581 -
Imprint:	New York, NY [u.a.] Elsevier 2021
DOI:	10.1016/j.ejps.2020.105581
Document Type:	Journal Article
Research Program:	Information Processing in Neuronal Networks
Link:	Published on 2020-10-06. Available in OpenAccess from 2021-10-06.
	Publikationsportal JuSER

Please use the identifier: http://dx.doi.org/10.1016/j.ejps.2020.105581 in citations.
Please use the identifier: http://hdl.handle.net/2128/26810 in citations.

Amyloid-β (Aβ) plays a central role in the development and progression of Alzheimer's disease (AD) with Aβ oligomers representing the most toxic species. The all-d-enantiomeric peptide RD2, which recently successfully completed clinical phase I, specifically eliminates Aβ oligomers in vitro as well as in vivo and improves cognitive deficits in various transgenic AD mouse models even after oral administration. To further enhance the oral absorption of RD2, folic acid has been conjugated to the d-peptide promoting an endocytosis-mediated uptake via a folate receptor located in the intestine. Two different conjugation strategies were selected to obtain prodrugs with folic acid being cleaved after intestinal absorption releasing unmodified RD2 in order to enable RD2's unaltered systemic efficacy. Both conjugates remained stable in simulated gastrointestinal fluids. But only one of them was suitable as prodrug as it was cleaved to RD2 in vitro in human blood plasma and liver microsomes and in vivo in mice after intravenous injection leading to a systemic release of RD2. Furthermore, the conjugate's permeability in vitro and after oral administration in mice was strongly enhanced compared to unconjugated RD2 demonstrating the prodrug's functionality. However, the conjugate seemed to have impaired the mice's wellbeing shortly after oral administration possibly resulting from strain-specific hypersensitivity to folic acid. Nevertheless, we assume that the prodrug is actually non-toxic, especially in lower concentrations as verified by a cell viability test. Furthermore, lower dosages can be applied with unaltered efficacy due to its enhanced oral absorption.