May 2003
Volume 44, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2003
Novel Dipeptide Prodrugs of Acyclovir for Ocular Herpes Infections
Author Affiliations & Notes
  • B.S. Anand
    Pharmacy, Univ MO-Kansas City, Kansas City, MO, United States
  • A.K. Mitra
    Pharmacy, Univ MO-Kansas City, Kansas City, MO, United States
  • Footnotes
    Commercial Relationships  B.S. Anand, None; A.K. Mitra, None.
  • Footnotes
    Support  RO1 EY09171;RO1 EY10659
Investigative Ophthalmology & Visual Science May 2003, Vol.44, 4753. doi:
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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)

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Abstract

Abstract: : 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.

Keywords: herpes simplex virus • antiviral drugs • anterior chamber 
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