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

Foley, David W., Pathak, Ravindra B., Phillips, Theresa R., Wilson, Gayle L., Bailey, Patrick D., Pieri, Myrtani, Senan, Anish and Meredith, David 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. 10.1016/j.ejmech.2018.06.064

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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 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: 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
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: Elsevier
ISSN: 0223-5234
Date of First Compliant Deposit: 11 July 2018
Date of Acceptance: 28 June 2018
Last Modified: 20 Oct 2019 00:32

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