Affinity of the antiviral enantiomers of oxathiolane cytosine nucleosides for human 2'-deoxycytidine kinase.
The two enantiomers of 2',3'-dideoxy-3'-thiacytidine (BCH-189) and their 5-fluoro analogs (FTC) were found to be good substrates for human 2'-deoxycytidine kinase with Km values in the 5.7 to 42.1 microM range. The affinity of the (-)-enantiomers was greater than that of the (+)-compounds. These results may explain the greater in vitro antiviral potency against human immunodeficiency virus and hepatitis B virus of the (-)-enantiomers when compared to their (+)-counterparts. The (+)- and (-)-enantiomers of FTC and BCH-189 are the first nucleoside analogs for which we have observed lower apparent kinetic constants for this enzyme in the presence of ATP compared to UTP.
Department of Pharmacology, University of Michigan, Ann Arbor 48109.
D S
DS
Shewach
D C
DC
Liotta
R F
RF
Schinazi
D000255:Adenosine Triphosphate / Q000378:metabolism; D000998:Antiviral Agents / Q000494:pharmacology*; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors; D003842:Deoxycytidine Kinase / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D019259:Lamivudine; D013237:Stereoisomerism; D014544:Uridine Triphosphate / Q000378:metabolism; D016047:Zalcitabine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000998:Antiviral Agents; D019259:Lamivudine; D016047:Zalcitabine; D000255:Adenosine Triphosphate; D003842:Deoxycytidine Kinase; D003564:Cytidine Deaminase; D014544:Uridine Triphosphate