Foley, D, Pathak, R, Phillips, TR, Wilson, G, Bailey, P, Pieri, M, Senan, A and Meredith, D (2018) Thiodipeptides targeting the intestinal oligopeptide transporter as a general approach to improving oral drug delivery. European Journal of Medicinal Chemistry, 156. pp. 180-189. ISSN 1768-3254

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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 showing 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: following oral dosing the intact prodrugs and free ibuprofen were measured in the plasma. This provides proof-of-concept for the idea of targeting poorly bioavailable drugs towards PepT1 transport as a general means of improving oral permeability.

Item Type: Article
Additional Information: This is the accepted author manuscript (AAM). The final published version (version of record) is available online via Elsevier at - please refer to any applicable terms of use of the publisher.
Uncontrolled Keywords: Prodrug, Membrane transporter, Intestine, PepT1, Drug delivery
Subjects: Q Science > QD Chemistry
Divisions: Faculty of Natural Sciences > School of Chemical and Physical Sciences
Depositing User: Symplectic
Date Deposited: 02 Jul 2018 08:37
Last Modified: 30 Jun 2019 01:30

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