In Vitro Activity And Transport Of Dipeptide Monoester Prodrugs Of Ganciclovir Across Isolated Rabbit Cornea

Abstract

Abstract: : Purpose:Ganciclovir (GCV), an acycloguanosine analog, was the first to show efficacy in HIV associated CMV retinitis, and is still the most commonly used anti–CMV drug. GCV has also been shown to demonstrate efficacy against herpes simplex virus type 1 (HSV–1). However, GCV being a hydrophilic compound has poor transcellular permeability across the blood retinal barrier, corneal epithelium as well as the gastrointestinal epithelium.The purpose of this study is to assess the affinity of the di–valine ester peptidomimetic prodrugs (e.g.Val–Val–GCV monoester), for the peptide transporters expressed on the corneal epithelium. Methods:Transport studies were carried out at 37^oC using isolated cornea. [³H]Gly–Sar was used as the model substrate for peptide transporters. Results:Valine ester prodrugs of GCV were synthesized in our laboratory. The prodrugs were seen to demonstrate sufficient stability in the transport buffers. Transport of [³H]Gly–Sar was inhibited by the dipeptide monoester prodrugs of GCV. Val–Val–GCV monoester was seen to demonstrate the highest affinity, amongst the prodrugs tested, for the peptide transporter expressed on the corneal epithelium. Transport of [³H]Gly–Sar across the cornea was decreased by almost 40% in the presence of Val–Val–GCV. Moreover, an increase in the total amount of GCV transport, across the corneal epithelium, was observed from equimolar quantities of the dipeptide GCV prodrugs. In vitro efficacy studies revealed that the Val–Val–GCV monoesters demonstrated high activity against HSV–1, HSV–2 and VZV and was at par or better than the standard acyclovir (ACV). Efficacy of Val–Val–GCVagainst CMV was equivalent to GCV. Conclusions:Our results indicate that Val–Val–GCV monoester prodrugs demonstrate high affinity for the peptide transporter expressed on the corneal epithelium. This dipeptide prodrug of GCV appears to possess better activity against HSV–1, HSV–2 and VZV compared to ACV. Considering these two factors, affinity and activity, Val–Val–GCV may provide tremendous benefits in the treatment of corneal keratitis.

Keywords: antiviral drugs • ion transporters • keratitis