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B.S. Anand, A.K. Mitra; Novel Dipeptide Prodrugs of Acyclovir for Ocular Herpes Infections . Invest. Ophthalmol. Vis. Sci. 2003;44(13):4753.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: A series of dipeptide prodrugs of antiviral nucleoside acyclovir (ACV) were designed to target the oligopeptide transporter on the cornea with an aim of improving the ocular bioavailability and therapeutic activity of ACV. Methods: Aqueous stability, ocular bioreversion kinetics in various tissues, in vitro/in vivo antiviral activity, cell proliferation assay and corneal transport characteristics of the dipeptide prodrugs were studied Results: ACV dipeptide prodrugs were found to be more stable at pH 5.6 in comparison to L-Val-ACV, an amino acid prodrug of ACV. Val-Val-ACV and Val-Tyr-ACV were found to have excellent antiviral activity against herpes simplex virus-1 (HSV-1). All the dipeptide prodrugs exhibited lower cytotoxicity as compared to currently approved anti-HSV agent, trifluorothymidine (TFT). Corneal permeabilities of all the ACV dipeptide prodrugs were observed to be higher than ACV.The dipeptide prodrug VVACV demonstrated excellent activity against HSV-1 in the rabbit epithelial and stromal keratitis models: 1% VVACV was as effective as 1% TFT at half the molar concentration (18.6 mM vs 33.3 mM, respectively). Conclusions: More permeable, less cytotoxic ACV dipeptide prodrugs exhibited excellent chemical stability and in vitro/in vivo antiviral activity against herpes simplex virus thereby rendering these lead compounds promising drug candidates against herpes virus infections.
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