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.
Highlights
More than 20 million people worldwide are affected by AD and the number of patients increases continuously[1,2]
For RD2’s lead compound D3, the superior resistance of all-D-enantiomeric peptides against metabolization by proteases and cytochrome P450 (CYP) enzymes contained in the gastrointestinal tract, blood and liver has recently been shown in a study by Elfgen and colleagues[24]
Activity and inhibition tests were performed with an enzyme specialized to metabolize D-enantiomeric amino acids, the human D-amino acid oxidase, which is mainly expressed in kidney, liver and brain[25,26,27,28]
Summary
More than 20 million people worldwide are affected by AD and the number of patients increases continuously[1,2]. Activity and inhibition tests were performed with an enzyme specialized to metabolize D-enantiomeric amino acids, the human D-amino acid oxidase (hDAAO), which is mainly expressed in kidney, liver and brain[25,26,27,28] It has previously been shown in preclinical toxicology studies, mandatory for the application of a phase I study in humans, that orally administered RD2 does not cause toxic effects up to high doses (complete study will be published elsewhere). Based on these findings, metabolite profiles of RD2 incubated in human liver microsomes were compared with metabolite profiles of RD2 incubated in liver microsomes of other species to identify potential human-specific metabolites and to forecast the safety for administration in humans[29].
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