Phosphorylation of ganciclovir phosphonate by cellular GMP kinase determines the stereoselectivity of anti-human cytomegalovirus activity.
A racemic mixture of ganciclovir phosphonate was resolved by stereoselective phosphorylation using GMP kinase. The R-enantiomer of ganciclovir phosphonate was active against human cytomegalovirus but the S-enantiomer was less active. We show that enantiomeric selectivity of antiviral for ganciclovir phosphonate was conferred by stereoselective phosphorylations by mammalian enzymes, not by stereoselective inhibition of DNA polymerase from human cytomegalovirus.
Miller
W H
WH
Glaxo Wellcome Inc., Research Triangle Park, NC 27709-3398, USA.
Beauchamp
L M
LM
Meade
E
E
Reardon
J E
JE
Biron
K K
KK
Smith
A A
AA
Goss
C A
CA
Miller
R L
RL
D000998:Antiviral Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects*; D015774:Ganciclovir / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D051528:Guanylate Kinases; D006801:Humans; D019384:Nucleic Acid Synthesis Inhibitors; D009703:Nucleoside-Phosphate Kinase / Q000737:chemistry* / Q000378:metabolism; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D019384:Nucleic Acid Synthesis Inhibitors; C087148:(3-((2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy)-4-hydroxybutyl)phosphonic acid; D017853:Phosphotransferases (Alcohol Group Acceptor); C075365:ganciclovir kinase; D009703:Nucleoside-Phosphate Kinase; D051528:Guanylate Kinases; D015774:Ganciclovir