Surprisingly high stability of the Aβ oligomer eliminating all-D-enantiomeric peptide D3 in media simulating the route of orally administered drugs

The aggregation of the amyloid beta protein (A beta) plays an important role in the pathology of Alzheimer's disease. Previously, we have developed the all-D-enantiomeric peptide D3, which is able to eliminate neurotoxic beta oligomers in vitro and improve cognition in a transgenic Alzheimer's disease mouse model in vivo even after oral administration. D-Peptides are expected to be more resistant against enzymatic proteolysis compared to their Lenantiomeric equivalents, and indeed, a pharmacokinetic study with tritiated D3 revealed the oral bioavailability to be about 58%. To further investigate the underlying properties, we examined the stability of D3 in comparison to its corresponding all-L-enantiomeric mirror image L-D3 in media simulating the gastrointestinal tract, blood and liver. Potential metabolization was followed by reversed-phase high-performance liquid chromatography. In simulated gastric fluid, D3 remained almost completely stable (89%) within 24 h, while 70% of L-D3 was degraded within the same time period. Notably, in simulated intestinal fluid, D3 also remained stable (96%) for 24 h, whereas L-D3 was completely metabolized within seconds. In human plasma and human liver microsomes, L-D3 was metabolized several hundred times faster than D3. The remarkably high stability may explain the high oral bioavailability seen in previous studies allowing oral administration of the drug candidate. Thus, all-D-enantiomeric peptides may represent a promising new compound class for drug development.