(+-)-(1 alpha,2 beta,3 alpha)-9-[2,3-bis(hydroxymethyl)-cyclobutyl] guanine [(+-)-BHCG or SQ 33,054]: a potent and selective inhibitor of herpesviruses.
(+-)-(1 alpha,2 beta,3 alpha)-9-[2,3-bis(hydroxymethyl)cyclobutyl] guanine [(+-)-BHCG or SQ 33,054] is a newly synthesized nucleoside analog with potent and selective antiviral activity against members of the herpesvirus group, including human cytomegalovirus. The activity against a thymidine kinase deficient HSV-2 mutant was 25-fold poorer than against the parent virus, suggesting that phosphorylation is an important prerequisite for antiviral activity against HSV-2. (+-)-BHCG is readily phosphorylated by purified HSV-1 thymidine kinase, and BHCG triphosphate synthesized enzymatically is a selective inhibitor of HSV-1 DNA polymerase. (+-)-BHCG did not inhibit host cell growth at concentrations at least 1000-fold higher than HSV-2 inhibitory concentrations. Subcutaneous administration of (+-)-BHCG was protective against HSV-1 systemic infections in mice. BHCG is an exciting antiviral agent and represents a new class of nucleoside analogs.
Field
A K
AK
Squibb Institute for Medical Research, Princeton, NJ 08543-4000.
Tuomari
A V
AV
McGeever-Rubin
B
B
Terry
B J
BJ
Mazina
K E
KE
Haffey
M L
ML
Hagen
M E
ME
Clark
J M
JM
Braitman
A
A
Slusarchyk
W A
WA
D000212:Acyclovir / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D004261:DNA Replication / Q000187:drug effects; D004259:DNA-Directed DNA Polymerase; D004285:Dogs; D005090:Exodeoxyribonucleases / Q000037:antagonists & inhibitors*; D005260:Female; D015774:Ganciclovir / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D006367:HeLa Cells / Q000187:drug effects; D006561:Herpes Simplex / Q000188:drug therapy; D006801:Humans; D051379:Mice; D019384:Nucleic Acid Synthesis Inhibitors; D010766:Phosphorylation; D018139:Simplexvirus / Q000187:drug effects* / Q000201:enzymology; D013937:Thymidine Kinase / Q000378:metabolism; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014780:Viruses / Q000187:drug effects
D000998:Antiviral Agents; D019384:Nucleic Acid Synthesis Inhibitors; D014764:Viral Proteins; D006147:Guanine; C063638:lobucavir; D013937:Thymidine Kinase; D004259:DNA-Directed DNA Polymerase; D005090:Exodeoxyribonucleases; C043417:DNA polymerase, Simplexvirus; D015774:Ganciclovir; D000212:Acyclovir