Broad-spectrum antiviral and cytocidal activity of cyclopentenylcytosine, a carbocyclic nucleoside targeted at CTP synthetase.
Cyclopentenylcytosine (Ce-Cyd) is a broad-spectrum antiviral agent active against DNA viruses [herpes (cytomegalo), pox (vaccinia)], (+)RNA viruses [picorna (polio, Coxsackie, rhino), toga (Sindbis, Semliki forest), corona], (-)RNA viruses [orthomyxo (influenza), paramyxo (parainfluenza, measles), arena (Junin, Tacaribe), rhabdo (vesicular stomatitis)] and (+/-)RNA viruses (reo). Ce-Cyd is a more potent antiviral agent than its saturated counterpart, cyclopentylcytosine (carbodine, C-Cyd). Ce-Cyd also has potent cytocidal activity against a number of tumor cell lines. The putative target enzyme for both the antiviral and antitumor action of Ce-Cyd is assumed to be the CTP synthetase that converts UTP to CTP. In keeping with this hypothesis was the finding that the antiviral and cytocidal effects of Ce-Cyd are readily reversed by Cyd and, to a lesser extent, Urd, but not by other nucleosides such as dThd or dCyd. In contrast, pyrazofurin and 6-azauridine, two nucleoside analogues that are assumed to interfere with OMP decarboxylase, another enzyme involved in the biosynthesis of pyrimidine ribonucleotides, potentiate the cytocidal activity of Ce-Cyd. Ce-Cyd should be further pursued, as such and in combination with OMP decarboxylase inhibitors, for its therapeutic potential in the treatment of both viral and neoplastic diseases.
De Clercq
E
E
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Murase
J
J
Marquez
V E
VE
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000577:Amides; D000998:Antiviral Agents / Q000494:pharmacology* / Q000633:toxicity; D001380:Azauridine / Q000494:pharmacology; D019731:Carbon-Nitrogen Ligases; D002455:Cell Division / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology; D003562:Cytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D003841:Deoxycytidine / Q000494:pharmacology; D004357:Drug Synergism; D005472:Fluorouracil / Q000494:pharmacology; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D008025:Ligases / Q000037:antagonists & inhibitors*; D009705:Nucleosides / Q000494:pharmacology; D011720:Pyrazoles; D012254:Ribavirin / Q000494:pharmacology; D012263:Ribonucleosides / Q000494:pharmacology; D012266:Ribose; D013936:Thymidine / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects; D014780:Viruses / Q000187:drug effects
D000577:Amides; D000998:Antiviral Agents; D009705:Nucleosides; D011720:Pyrazoles; D012263:Ribonucleosides; D003561:Cytarabine; D003841:Deoxycytidine; D012254:Ribavirin; C002997:pyrazofurin; D014498:Uracil; D003562:Cytidine; D012266:Ribose; C045911:cyclopentenyl cytosine; C033357:carbodine; C031096:neplanocin A; D001380:Azauridine; C068989:cyclopentenyluracil; D008025:Ligases; D019731:Carbon-Nitrogen Ligases; C019951:CTP synthetase; D000241:Adenosine; D005472:Fluorouracil; D013936:Thymidine