Thiodipeptides targeting the intestinal oligopeptide transporter as a general approach to improving oral drug delivery

European Journal of Medicinal Chemistry
David FoleyD Meredith

Abstract

The broad substrate capacity of the intestinal oligopeptide transporter, PepT1, has made it a key target of research into drug delivery. Whilst the substrate capacity of this transporter is broad, studies have largely been limited to small peptides and peptide-like drugs. Here, we demonstrate for the first time that a diverse range of drugs can be targeted towards transport by PepT1 using a hydrolysis resistant carrier. Eleven prodrugs were synthesized by conjugating modified dipeptides containing a thioamide bond to the approved drugs ibuprofen, gabapentin, propofol, aspirin, acyclovir, nabumetone, atenolol, zanamivir, baclofen and mycophenolate. Except for the aspirin and acyclovir prodrugs, which were unstable in the assay conditions and were not further studied, the prodrugs were tested for affinity and transport by PepT1 expressed in Xenopus laevis oocytes: binding affinities ranged from approximately 0.1 to 2 mM. Compounds which showed robust transport in an oocyte trans-stimulation assay were then tested for transcellular transport in Caco-2 cell monolayers: all five tested prodrugs showed significant PepT1-mediated transcellular uptake. Finally, the ibuprofen and propofol prodrugs were tested for absorption in rats: fol...Continue Reading

Citations

Dec 22, 2020·Bioorganic & Medicinal Chemistry Letters·Dan LouShihui Bao
Mar 13, 2020·European Journal of Medicinal Chemistry·Steffan Willetts, David W Foley
Feb 24, 2021·Journal of Colloid and Interface Science·Fei PengFeng Qiu
Mar 11, 2021·Current Opinion in Chemical Biology·Andrea CasiraghiGiulio Superti-Furga
Jan 1, 2020·Molecular Therapy. Methods & Clinical Development·Kanae KawaiHiroyuki Mizuguchi

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Methods Mentioned

BETA
NMR
column chromatography

Software Mentioned

DataApex
ChEMBL

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