Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Mol Pharm
2010 Dec 06;76:2349-61. doi: 10.1021/mp100186b.
Show Gene links
Show Anatomy links
Serine side chain-linked peptidomimetic conjugates of cyclic HPMPC and HPMPA: synthesis and interaction with hPEPT1.
Peterson LW
,
Sala-Rabanal M
,
Krylov IS
,
Serpi M
,
Kashemirov BA
,
McKenna CE
.
???displayArticle.abstract???
Cidofovir (HPMPC), a broad spectrum antiviral agent, cannot be administered orally due to ionization of its phosphonic acid group at physiological pH. One prodrug approach involves conversion to the cyclic form (cHPMPC, 1) and esterification by the side chain hydroxyl group of a peptidomimetic serine. Transport studies in a rat model have shown enhanced levels of total cidofovir species in the plasma after oral dosing with L-Val-L-Ser-OMe cHPMPC, 2a. To explore the possibility that 2a and its three L/D stereoisomers 2b-d undergo active transport mediated by the peptide-specific intestinal transporter PEPT1, we performed radiotracer uptake and electrophysiology experiments applying the two-electrode voltage clamp technique in Xenopus laevis oocytes overexpressing human PEPT1 (hPEPT1, SLC15A1). 2a-d did not induce inward currents, indicating that they are not transported, but the stereoisomers with an L-configuration at the N-terminal valine (2a and 2b) potently inhibited transport of the hPEPT1 substrate glycylsarcosine (Gly-Sar). A "reversed" dipeptide conjugate, L-Ser-L-Ala-OiPr cHPMPC (4), also did not exhibit detectable transport, but completely abolished the Gly-Sar signal, suggesting that affinity of the transporter for these prodrugs is not impaired by a proximate linkage to the drug in the N-terminal amino acid of the dipeptide. Single amino acid conjugates of cHPMPC (3a and 3b) or cHPMPA (5, 6a and 6b) were not transported and only weakly inhibited Gly-Sar transport. The known hPEPT1 prodrug substrate valacyclovir (7) and its L-Val-L-Val dipeptide analogue (8) were used to verify coupled transport by the oocyte model. The results indicate that the previously observed enhanced oral bioavailability of 2a relative to the parent drug is unlikely to be due to active transport by hPEPT1. Syntheses of the novel compounds 2b-d and 3-6 are described, including a convenient solid-phase method to prepare 5, 6a and 6b.
Anastasi,
New antiviral nucleoside prodrugs await application.
2003, Pubmed
Anastasi,
New antiviral nucleoside prodrugs await application.
2003,
Pubmed
Balimane,
Direct evidence for peptide transporter (PepT1)-mediated uptake of a nonpeptide prodrug, valacyclovir.
1998,
Pubmed
,
Xenbase
De Clercq,
Clinical potential of the acyclic nucleoside phosphonates cidofovir, adefovir, and tenofovir in treatment of DNA virus and retrovirus infections.
2003,
Pubmed
Dressman,
Towards quantitative prediction of oral drug absorption.
2008,
Pubmed
Eriksson,
Serine peptide phosphoester prodrugs of cyclic cidofovir: synthesis, transport, and antiviral activity.
2008,
Pubmed
Foley,
The in vitro transport of model thiodipeptide prodrugs designed to target the intestinal oligopeptide transporter, PepT1.
2009,
Pubmed
Guo,
Interactions of a nonpeptidic drug, valacyclovir, with the human intestinal peptide transporter (hPEPT1) expressed in a mammalian cell line.
1999,
Pubmed
Han,
5'-Amino acid esters of antiviral nucleosides, acyclovir, and AZT are absorbed by the intestinal PEPT1 peptide transporter.
1998,
Pubmed
Hostetler,
Alkoxyalkyl prodrugs of acyclic nucleoside phosphonates enhance oral antiviral activity and reduce toxicity: current state of the art.
2009,
Pubmed
Kottra,
Inhibition of intracellular dipeptide hydrolysis uncovers large outward transport currents of the peptide transporter PEPT1 in Xenopus oocytes.
2009,
Pubmed
,
Xenbase
Larsen,
QSAR models for the human H(+)/peptide symporter, hPEPT1: affinity prediction using alignment-independent descriptors.
2008,
Pubmed
Liang,
Human intestinal H+/peptide cotransporter. Cloning, functional expression, and chromosomal localization.
1995,
Pubmed
,
Xenbase
Loo,
How drugs interact with transporters: SGLT1 as a model.
2008,
Pubmed
,
Xenbase
Mackenzie,
Mechanisms of the human intestinal H+-coupled oligopeptide transporter hPEPT1.
1996,
Pubmed
,
Xenbase
Mendel,
Conversion of 1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosine to cidofovir by an intracellular cyclic CMP phosphodiesterase.
1997,
Pubmed
Nashed,
Synthesis and characterization of novel dipeptide ester prodrugs of acyclovir.
2003,
Pubmed
Pedretti,
Modeling of the intestinal peptide transporter hPepT1 and analysis of its transport capacities by docking and pharmacophore mapping.
2008,
Pubmed
Peterson,
Prodrug approaches to improving the oral absorption of antiviral nucleotide analogues.
2009,
Pubmed
Rubio-Aliaga,
Peptide transporters and their roles in physiological processes and drug disposition.
2008,
Pubmed
Sala-Rabanal,
Molecular interactions between dipeptides, drugs and the human intestinal H+ -oligopeptide cotransporter hPEPT1.
2006,
Pubmed
,
Xenbase
Sala-Rabanal,
Molecular mechanism of dipeptide and drug transport by the human renal H+/oligopeptide cotransporter hPEPT2.
2008,
Pubmed
,
Xenbase
Talluri,
Synthesis, metabolism and cellular permeability of enzymatically stable dipeptide prodrugs of acyclovir.
2008,
Pubmed
Winiwarter,
Modeling of drug-transporter interactions using structural information.
2008,
Pubmed
