N2-phenyldeoxyguanosine: a novel selective inhibitor of herpes simplex thymidine kinase.
A series of N2-substituted guanine derivatives was screened against mammalian thymidine kinase and the thymidine kinase encoded by type I herpes simplex virus to examine their capacity to selectivity inhibit the viral enzyme. Several bases, nucleosides, and nucleotides displayed selective activity. The mechanism of action of the most potent derivative, N2-phenyl-2'-deoxyguanosine (PhdG) was studied in detail. PhdG (a) inhibited the viral enzyme competitively with respect to the substrates thymidine and deoxycytidine, (b) was completely resistant to phosphorylation, (c) displayed limited toxicity for the HeLa cell lines employed as hosts for viral infection, and (d) selectively inhibited viral thymidine kinase function in intact cultured cells. The results indicate that the PhdG drug prototype has potential as a selective anti-herpes agent and as a novel molecular probe of the structure and function of herpes simplex thymidine kinase.
Focher
F
F
Istituto di Genetica Biochimica ed Evoluzionistica, CNR, Pavia, Italy.
Hildebrand
C
C
Freese
S
S
Ciarrocchi
G
G
Noonan
T
T
Sangalli
S
S
Brown
N
N
Spadari
S
S
Wright
G
G
D000998:Antiviral Agents / Q000138:chemical synthesis*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation; D018139:Simplexvirus / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors*
D000998:Antiviral Agents; C056703:N(2)-phenyl-2'-deoxyguanosine; D006147:Guanine; D013937:Thymidine Kinase; D003849:Deoxyguanosine