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- W2897495489 abstract "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 PRI-002, currently in clinical phase I, specifically eliminates Aβ oligomers in vitro as well as in vivo and improves cognition in various transgenic AD mouse models even after oral administration. To further enhance oral absorption of PRI-002, folic acid has been conjugated enabling an uptake mediated by the folate receptor alpha (FRα) located in the colon and rectum. Fol-PRI-002 is designed as prodrug with folic acid being cleaved after intestinal absorption releasing unmodified PRI-002 in order to enable PRI-002’s unaltered systemic efficacy. Cleavage of the conjugate was examined by HPLC and MS in vitro in media simulating the gastrointestinal tract, blood and liver as well as in vivo in blood samples taken after intravenous injection in mice. The permeability of the conjugate compared to unconjugated PRI-002 was investigated in a FRα expressing cell model of the intestinal barrier. Fol-PRI-002 remained stable in simulated gastric fluid and was only slowly metabolized to PRI-002 in simulated intestinal fluid within hours enabling the oral administration of the prodrug. Folic acid has also been cleaved upon incubation with liver microsomes and blood as well as in vivo after i.v. injection leading to a systemic release of PRI-002. The intestinal permeability of Fol-PRI-002 was sevenfold enhanced compared to unmodified PRI-002 demonstrating the prodrug's functionality. These experiments indicate that conjugation with folic acid is advantageous for intestinal absorption of PRI-002 and that the conjugated folic acid is systemically cleavable enabling an unaltered drug efficacy." @default.
- W2897495489 created "2018-10-26" @default.
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- W2897495489 date "2018-07-01" @default.
- W2897495489 modified "2023-10-16" @default.
- W2897495489 title "P4‐213: ORAL ABSORPTION ENHANCEMENT OF THE AMYLOID‐β OLIGOMER ELIMINATING COMPOUND PRI‐002 BY CONJUGATION WITH FOLIC ACID" @default.
- W2897495489 doi "https://doi.org/10.1016/j.jalz.2018.07.034" @default.
- W2897495489 hasPublicationYear "2018" @default.
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