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

Journal article


Foley, D, Pathak, R, Phillips, T, Wilson, G, Bailey, PD, 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.
AuthorsFoley, D, Pathak, R, Phillips, T, Wilson, G, Bailey, PD, Pieri, M, Senan, A and Meredith, D
Abstract

The broad substrate capacity of the intestinal oligopeptide transporter, PepT1, has made it a key target of re- search 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. Ex- cept 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.

KeywordsProdrug; Membrane transporter; Intestine; PepT1; Drug delivery
Year2018
JournalEuropean Journal of Medicinal Chemistry
Journal citation156, pp. 180-189
PublisherElsevier
ISSN0223-5234
Digital Object Identifier (DOI)doi:10.1016/j.ejmech.2018.06.064
FunderWellcome Trust
Publication dates
Print30 Jun 2018
Publication process dates
Deposited06 Jul 2018
Accepted28 Jun 2018
Accepted author manuscript
License
CC BY-NC-ND 4.0
File description
Article
Supplemental file
License
CC BY 4.0
File description
Reproduced NMR Spectra for Key Compounds
Permalink -

https://openresearch.lsbu.ac.uk/item/86q52

  • 7
    total views
  • 35
    total downloads
  • 1
    views this month
  • 1
    downloads this month

Related outputs

A Modular Synthesis of Multidentate S-, N- and O-Containing Meta- and Paracyclophanes
Rasheed, OK, Bailey, PD, Lawrence, A, Quayle, P and Raftery, J (2015). A Modular Synthesis of Multidentate S-, N- and O-Containing Meta- and Paracyclophanes. European Journal of Organic Chemistry. 2015 (32), pp. 6988 - 6993.
A Modular Approach to Functionalised Dyes
Rasheed, OK, Lawrence, A, Quayle, P and Bailey, PD (2015). A Modular Approach to Functionalised Dyes. Synlett. 27 (6), pp. 905 - 911.
A cyclosporine derivative is a substrate of the oligopeptide transporter PepT1
Bailey, PD, Foley, D, Bermudez, I and Meredith, D (2016). A cyclosporine derivative is a substrate of the oligopeptide transporter PepT1. MedChemComm. 7 (5), pp. 999 - 1002.