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.
Shewach
D S
DS
Department of Pharmacology, University of Michigan, Ann Arbor 48109.
Liotta
D C
DC
Schinazi
R F
RF
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