Open AccessActivation and Deactivation of a Broad-Spectrum Antiviral Drug by a Single Enzyme: Adenosine Deaminase Catalyzes Two Consecutive Deamination Reactions
Author(s) -
Jim Zhen Wu,
Heli Walker,
Johnson Y.N. Lau,
Zhi Hong
Publication year - 2003
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.47.1.426-431.2003
Subject(s) - ribavirin , deamination , adenosine deaminase , prodrug , nucleoside , chemistry , pharmacology , adenosine , antiviral drug , drug , enzyme , biochemistry , biology , genotype , gene
Ribavirin is an approved broad-spectrum antiviral drug. A liver-targeting prodrug of ribavirin, viramidine, is in clinical trial in an attempt to provide a better therapeutic index. The conversion of viramidine to ribavirin, and of ribavirin to an inactive metabolite through adenosine deaminase, is reported. Kinetic analysis indicates that adenosine deaminase is likely involved in activation of viramidine in vivo, and the process is highly pH sensitive. The differential activities of two consecutive deamination reactions are kinetically studied and interpreted based on adenosine deaminase structural information. A comprehensive understanding of the viramidine and ribavirin deamination mechanism should help in designing better nucleoside therapeutics in the future.