The in vitro transport of model thiodipeptide prodrugs designed to target the intestinal oligopeptide transporter, PepT1

Foley, David W.; Pieri, Myrtani; Pettecrew, Rachel; Price, Richard A.; Miles, Stephen; Lam, Ho Kam; Bailey, Patrick D.; Meredith, David

doi:10.1039/b909221h

Cited by 18 publications

(32 citation statements)

References 53 publications

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“…In this paper, we apply the results of our previously reported characterisation of the structure-transport relationships for PepT1 [ 15 ] to drug delivery challenges and report proof-of-concept studies that validate the use of our thiodipeptide carriers as a general approach for targeting a variety of drugs towards PepT1 mediated transport. We focused on two major areas that we felt could benefit from our thiodipeptide drug delivery technology: Drugs with GI side effects .…”

Section: Introductionmentioning

confidence: 89%

“…There are many examples of targeting PepT1 to improve the oral bioavailability of pharmacologically active compounds, usually by modifying them so that they resemble the natural di- or tripeptide substrates [ [8] , [9] , [10] , [11] , [12] , [13] ]. We have patented [ 14 ] a set of thiodipeptide substrates (such as A and B ) that we hope can act as “carriers” for drug transport by PepT1 generally, and have previously published our work on model systems demonstrating that a variety of linkers can be employed [ 15 , 16 ]. The basic premise is illustrated in Fig.…”

Section: Introductionmentioning

confidence: 99%

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

Foley

Pathak

Phillips

et al. 2018

European Journal of Medicinal Chemistry

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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.

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Section: Introductionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

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

Foley

Pathak

Phillips

et al. 2018

European Journal of Medicinal Chemistry

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“…48, 49 Efforts to define the structure-activity relationship (SAR) and structure-transport relationship (STR) properties of hPEPT1 have been made, 50–53 however, reliable predictive rules for affinity and transport have been elusive. 54 In a search for a promoiety that, when conjugated to the phosphonate drug, can be recognized and translocated by hPEPT1, and also efficiently cleaved from the prodrug at the target site in vivo , various ethylene glycol (EG)-linked amino acid prodrugs and dipeptide prodrugs of cyclic ( S )-HPMPC (Figure 5; 5−12 ) have been previously reported as discussed in the following section.…”

Section: The Rationale: Why Amino Acids?mentioning

confidence: 99%

Evolution of an Amino Acid Based Prodrug Approach: Stay Tuned

et al. 2013

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Certain acyclic nucleoside phosphonates (ANPs) such as (S)-HPMPC (cidofovir, Vistide®) and (S)-HPMPA have been shown to be active against a broad spectrum of DNA and retroviruses. However, their poor absorption as well as their toxicity limit the utilization of these therapeutics in the clinic. Nucleoside phosphonates are poorly absorbed primarily due to the presence of the phosphonic acid group, which ionizes at physiological pH. When dosed intravenously they display dose-limiting nephrotoxicity due to their accumulation in the kidney. To overcome these limitations, nucleoside phosphonate prodrug strategies have taken center stage in the development pathway and a number of different approaches are at various stages of development. Our efforts have focused on the development of ANP prodrugs in which a benign amino acid promoiety masks a phosphonate P-OH via a hydroxyl side chain. The design of these prodrugs incorporates multiple chemical groups (the P−X−C linkage, the amino acid stereochemistry, the C-terminal and N-terminal functional groups) that can be been tuned to modify absorption, pharmacokinetic and efficacy properties with the goal of improving overall prodrug performance.

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“…Some endothioxopeptides are effective carrier systems for drugs with affinity for the intestinal peptide transporter PepT1 …”

Section: Introductionmentioning

confidence: 99%

Endothioxopeptides: A conformational overview

et al. 2016

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Although thionamides would have been first prepared two centuries ago and their chemical and spectroscopic properties extensively investigated, only much more recently (since about 1985) a well deserved but still insufficient attention has been paid to their endothioxopeptide subfamily which nonetheless currently represents a rapidly emerging area of great scientific interest in the broader field of foldameric compounds based on biologically relevant building blocks. After two brief sections offering information on the unfortunately still limited number of endothioxopeptides discovered from natural sources but also on the impressive advancements registered in the last few years in their synthetic methods, this review article outlines the results of a detailed literature survey on the ongoing great, but not systematic, progress related to the conformational consequences generated by incorporating one (or more) thionamide group(s) into a polypeptide chain. Finally, a short discussion of the growing, but still in its infancy, class of the endoselenoxopeptide congeners is also presented.

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The in vitro transport of model thiodipeptide prodrugs designed to target the intestinal oligopeptide transporter, PepT1

Abstract: A thiodipeptide carrier system is shown to be effective at enabling a range of covalently bound molecules, including benzyl, benzoyl and ibuprofen conjugates, to be transported via the intestinal peptide transporter PepT1, demonstrating its potential as a rational drug delivery target.

Cited by 18 publications

References 53 publications

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

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

Evolution of an Amino Acid Based Prodrug Approach: Stay Tuned

Endothioxopeptides: A conformational overview

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