Activation and deactivation of a broad-spectrum antiviral drug by a single enzyme: adenosine deaminase catalyzes two consecutive deamination reactions.
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.
Wu
Jim Zhen
JZ
Research & Development, Ribapharm Corporation, Costa Mesa, California 92626, USA. jwu@icnpharm.com
Walker
Heli
H
Lau
Johnson Y N
JY
Hong
Zhi
Z
D000243:Adenosine Deaminase / Q000737:chemistry*; D003641:Deamination; D006863:Hydrogen-Ion Concentration; D011355:Prodrugs / Q000737:chemistry; D012254:Ribavirin / Q000031:analogs & derivatives / Q000737:chemistry* / Q000493:pharmacokinetics*; D013379:Substrate Specificity
D011355:Prodrugs; D012254:Ribavirin; D000243:Adenosine Deaminase; C026956:taribavirin