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Novel dipeptide prodrugs of acyclovir for ocular herpes infections: Bioreversion, antiviral activity and transport across rabbit cornea.
Curr Eye Res 2003 Mar-Apr; 26(3-4):151-63CE

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 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. The prodrugs exhibited higher solubility than 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). Transport of [(3)H] Val-ACV was inhibited significantly in the presence of the dipeptide prodrugs of ACV. Corneal permeabilities of all the ACV dipeptide prodrugs were observed to be higher than ACV possibly due to recognition of the prodrugs by the oligopeptide transporter on the cornea.

CONCLUSIONS

The dipeptide prodrugs were found to be more permeable than the parent drug, ACV. More permeable, less cytotoxic ACV dipeptide prodrugs exhibited excellent chemical stability and antiviral activity against herpes simplex virus thereby rendering these lead compounds promising drug candidates against herpes virus infections.

Authors+Show Affiliations

Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USANo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12815543

Citation

Anand, Banmeet, et al. "Novel Dipeptide Prodrugs of Acyclovir for Ocular Herpes Infections: Bioreversion, Antiviral Activity and Transport Across Rabbit Cornea." Current Eye Research, vol. 26, no. 3-4, 2003, pp. 151-63.
Anand B, Nashed Y, Mitra A. Novel dipeptide prodrugs of acyclovir for ocular herpes infections: Bioreversion, antiviral activity and transport across rabbit cornea. Curr Eye Res. 2003;26(3-4):151-63.
Anand, B., Nashed, Y., & Mitra, A. (2003). Novel dipeptide prodrugs of acyclovir for ocular herpes infections: Bioreversion, antiviral activity and transport across rabbit cornea. Current Eye Research, 26(3-4), pp. 151-63.
Anand B, Nashed Y, Mitra A. Novel Dipeptide Prodrugs of Acyclovir for Ocular Herpes Infections: Bioreversion, Antiviral Activity and Transport Across Rabbit Cornea. Curr Eye Res. 2003;26(3-4):151-63. PubMed PMID: 12815543.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel dipeptide prodrugs of acyclovir for ocular herpes infections: Bioreversion, antiviral activity and transport across rabbit cornea. AU - Anand,Banmeet, AU - Nashed,Yasser, AU - Mitra,Ashim, PY - 2003/6/20/pubmed PY - 2003/9/23/medline PY - 2003/6/20/entrez SP - 151 EP - 63 JF - Current eye research JO - Curr. Eye Res. VL - 26 IS - 3-4 N2 - 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 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. The prodrugs exhibited higher solubility than 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). Transport of [(3)H] Val-ACV was inhibited significantly in the presence of the dipeptide prodrugs of ACV. Corneal permeabilities of all the ACV dipeptide prodrugs were observed to be higher than ACV possibly due to recognition of the prodrugs by the oligopeptide transporter on the cornea. CONCLUSIONS: The dipeptide prodrugs were found to be more permeable than the parent drug, ACV. More permeable, less cytotoxic ACV dipeptide prodrugs exhibited excellent chemical stability and antiviral activity against herpes simplex virus thereby rendering these lead compounds promising drug candidates against herpes virus infections. SN - 0271-3683 UR - https://www.unboundmedicine.com/medline/citation/12815543/Novel_dipeptide_prodrugs_of_acyclovir_for_ocular_herpes_infections:_Bioreversion_antiviral_activity_and_transport_across_rabbit_cornea_ L2 - http://www.tandfonline.com/doi/full/10.1076/ceyr.26.3.151.14893 DB - PRIME DP - Unbound Medicine ER -