Deoxycytidine deaminase-resistant stereoisomer is the active form of (+/-)-2',3'-dideoxy-3'-thiacytidine in the inhibition of hepatitis B virus replication.
2',3'-Dideoxy-3'-thiacytidine (+/-)-SddC) was found to have potent activity against human hepatitis B virus as well as human immunodeficiency viruses in culture. The (-)form ((-)-SddC) which is resistant to deoxycytidine deaminase was found to be the more active antiviral stereoisomer than the (+)-form ((+)-SddC). The (+)-SddC is susceptible to deamination by deoxycytidine deaminase and is 25- and 12-fold more toxic than (-)-SddC in CEM cells in terms of anti-cell growth and anti-mitochondrial DNA synthesis, respectively. Similar results were obtained using a mixture of their 5-fluoro analogs ((+/-)-FSddC). Unlike 2',3'-dideoxycytidine, which is a potent inhibitor of mitochondrial DNA synthesis and results in such delayed toxicity as peripheral neuropathy with long term usage, (-)-SddC does not affect mitochondrial DNA synthesis. The (-)form is phosphorylated to (-)-SddCMP and is subsequently converted to (-)-SddCDP and (-)-SddCTP. One additional major metabolite which has been tentatively assigned the name "(-)-SddCMP sialate" was also identified. No significant difference in terms of the profiles of the metabolites was found between 4 and 24 h. There is an appreciable amount of (-)-SddCTP detectable 24 h after removal of the drug. (-)-SddCTP was also found to be approximately 3-fold more potent than (+)-SddCTP in inhibiting human hepatitis B virus DNA polymerase. This is the first nucleoside analog with the unnatural sugar configuration demonstrated to have antiviral activity.
Chang
C N
CN
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510.
Doong
S L
SL
Zhou
J H
JH
Beach
J W
JW
Jeong
L S
LS
Chu
C K
CK
Tsai
C H
CH
Cheng
Y C
YC
Liotta
D
D
Schinazi
R
R
D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D003564:Cytidine Deaminase; D004261:DNA Replication / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000096:biosynthesis; D006515:Hepatitis B virus / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D019259:Lamivudine; D009700:Nucleoside Deaminases / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014162:Transfection; D016047:Zalcitabine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D000998:Antiviral Agents; D004272:DNA, Mitochondrial; D019259:Lamivudine; D016047:Zalcitabine; D009700:Nucleoside Deaminases; D003564:Cytidine Deaminase; C011530:deoxycytidine deaminase