Specificity of a prodrug-activating enzyme hVACVase: The leaving group effect

Jing Sun, Arik Dahan, Zachary F. Walls, Longsheng Lai, Kyung Dall Lee, Gordon L. Amidon

    Research output: Contribution to journalArticlepeer-review

    14 Scopus citations


    Human valacyclovirase (hVACVase) is a prodrug-activating enzyme for amino acid prodrugs including the antiviral drugs valacyclovir and valganciclovir. In hVACVase-catalyzed reactions, the leaving group of the substrate corresponds to the drug moiety of the prodrug, making the leaving group effect essential for the rational design of new prodrugs targeting hVACVase activation. In this study, a series of valine esters, phenylalanine esters, and a valine amide were characterized for the effect of the leaving group on the efficiency of hVACVase-mediated prodrug activation. Except for phenylalanine methyl and ethyl esters, all of the ester substrates exhibited a relatively high specificity constant (kcat/Km), ranging from 850 to 9490 mM -1•s-1. The valine amide Val-3-APG exhibited significantly higher Km and lower kcat values compared to the corresponding ester Val-3-HPG, indicating poor specificity for hVACVase. In conclusion, the substrate leaving group has been shown to affect both binding and specific activity of hVACVase-catalyzed activation. It is proposed that hVACVase is an ideal target for α-amino acid ester prodrugs with relatively labile leaving groups while it is relatively inactivate toward amide prodrugs.

    Original languageEnglish
    Pages (from-to)2362-2368
    Number of pages7
    JournalMolecular Pharmaceutics
    Issue number6
    StatePublished - 6 Dec 2010

    ASJC Scopus subject areas

    • Molecular Medicine
    • Pharmaceutical Science
    • Drug Discovery


    Dive into the research topics of 'Specificity of a prodrug-activating enzyme hVACVase: The leaving group effect'. Together they form a unique fingerprint.

    Cite this