Analysis of phosphorylation pathways of antiherpesvirus nucleosides by varicella-zoster virus-specific enzymes.
The inhibitory activities of acyclovir (ACV), 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil (BV-araU), ganciclovir (GCV), 9-(2-deoxy-2-hydroxymethyl-beta-D-erythro-oxetanosyl)guanine (OXT-G), and (+)-9-[(1R,2R,3S)-2,3-bis(hydroxymethyl)Cyclobutyl]guanine (cOXT-G) on the replication of wild-type and thymidine kinase (TK)-negative strains of herpes simplex virus types 1 and 2 and varicella-zoster virus (VZV) and the wild-type strain of human cytomegalovirus were tested to clarity whether the phosphorylation of these compounds is catalyzed by viral TK or other enzymes. ACV and BV-araU had little effect on the replication of TK-negative virus strains. On the other hand, GCV, OXT-G, and cOXT-G inhibited the replication of TK-negative VZV at concentrations 10 times higher than those at which they inhibited wild-type VZV, indicating that a kinase other than TK phosphorylates GCV and OXT-G in VZV-infected cells. GCV phosphorylation activity was not detected in VZV-infected cell lysates; therefore, this activity was evaluated in COS 1 cells expressing viral TK and viral protein kinase (PK). The COS 1 cells expressing VZV TK were shown to be susceptible to all compounds tested. In contrast, VZV Pk-expressing COS 1 cells were susceptible to only GCV, OXT-G, and cOXT-G. These results suggest that VZV PK phosphorylates some nucleoside analogs, for example, GCV, OXT-G, and cOXT-G. This phosphorylation pathway may be important in the anti-VZV activities of some nucleoside analogs.
Koyano
S
S
Department of Microbiology, Asahikawa Medical College, Japan.
Suzutani
T
T
Yoshida
I
I
Azuma
M
M
D000212:Acyclovir / Q000378:metabolism / Q000494:pharmacology; D000998:Antiviral Agents / Q000378:metabolism* / Q000494:pharmacology; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D002455:Cell Division; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects / Q000201:enzymology; D015774:Ganciclovir / Q000378:metabolism* / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D006564:Herpesviridae / Q000187:drug effects / Q000201:enzymology; D014645:Herpesvirus 3, Human / Q000187:drug effects / Q000201:enzymology*; D006801:Humans
D000998:Antiviral Agents; C057479:oxetanocin G; D001086:Arabinofuranosyluracil; D006147:Guanine; C031368:sorivudine; D015774:Ganciclovir; D000212:Acyclovir