Inhibition of herpesvirus-induced thymidine kinase and DNA polymerase by beta-hydroxynorvaline.
Treatment of HSV-infected cells with 5-10 mM beta-hydroxynorvaline (Hnv), a threonine analog, specifically affects herpesvirus DNA replication: both the rate of and total DNA synthesis are reduced, the former approximately 15-fold by Hnv (6 h post-infection) and the latter by 12-fold (between 3 and 12 h post-infection). The effect on DNA replication was due to inhibition of HSV-1 thymidine kinase (TK) and DNA polymerase (DP) activities; the former is reduced by 75% and whereas DP returns to baseline levels (when compared to untreated and/or uninfected cells). Host cell TK and DP activities are unaffected. It is suggested that beta-hydroxynorvaline is incorporated into these enzyme(s), either close to or at the active site thus perturbing viral DNA synthesis. beta-Hydroxynorvaline should have unique utility as a targeted antiviral compound, acting on both membrane-mediated phenomena (fusion, penetration and attachment) and DNA replication.
Massare
M J
MJ
Department of Ophthalmology, University of Pennsylvania, School of Medicine, Philadelphia 19104.
Blough
H A
HA
D002460:Cell Line; D004279:DNA, Viral / Q000096:biosynthesis*; D019384:Nucleic Acid Synthesis Inhibitors; D018139:Simplexvirus / Q000201:enzymology*; D013912:Threonine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors*
D004279:DNA, Viral; D019384:Nucleic Acid Synthesis Inhibitors; C010994:3-hydroxynorvaline; D013912:Threonine; D013937:Thymidine Kinase