Acyclovir resistance in herpes simplex virus type 1: biochemical and functional studies on the thymidine kinase of the highly resistant R100 strain.
The biochemical and functional properties of the thymidine kinase (TK) of the herpes simplex virus type 1 mutant R100, that is highly resistant to 9-(2-hydroxyethoxymethyl)guanine (acyclovir), are reported in comparison with the properties of its parental strain, wt. The mutant induced the production of a TK activity that accounted for only 10% of the wt one. This feature was not apparently related to a defective expression of the TK gene but it was rather connected to some functional characteristics of R100 enzyme. Although affinities of this enzyme for ATP and thymidine were unchanged, apparent Vmax values for thymidine were much reduced. In addition, affinities for antiviral analogues acyclovir, 9-(1,3-dihydroxymethyl)guanine (DHPG), 5-(2-bromovinyl)2'-deoxyuridine (BVdU), and 5-iodo-2'deoxycytidine (IdCyd) were drastically diminished (between 50-fold and more than 100-fold). This mutation therefore seems to affect the active site of the enzyme which is involved in the catalytic conversion of thymidine and in the binding of the analogues. The above features of HSV-1 R100 seem quite distinct from those of previously described HSV-1 resistant mutants.
Palú
G
G
Institute of Microbiology, University of Padova Medical School, Italy.
Bevilacqua
F
F
Biasolo
M A
MA
Parolin
C
C
Tognon
M
M
Romanelli
M G
MG
Meloni
G A
GA
D000212:Acyclovir / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D004352:Drug Resistance, Microbial / Q000235:genetics; D007700:Kinetics; D009154:Mutation; D018139:Simplexvirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism*
D013937:Thymidine Kinase; D000212:Acyclovir