Some 6-aza-5-substituted-2'-deoxyuridines show potent and selective inhibition of herpes simplex virus type 1 thymidine kinase.
The synthesis and X-ray crystal structures of a series of 5-substituted-6-aza-2'-deoxyuridines is reported. These nucleoside analogues inhibit the phosphorylation of thymidine by HSV-1 TK but have no effect on the corresponding human enzyme. Detailed examination of one analogue proves it to be a competitive inhibitor of thymidine with a Ki of 0.34 microM and is a very poor substrate. The analogues are not substrates for the enzyme and also do not inhibit the degradation of thymidine by thymidine phosphorylase. Molecular modelling showed that the inhibitors fit well in the active site of HSV-1 TK, provided the conformation of the sugar moiety is the same for thymidine in the complex.
School of Chemistry, University of Birmingham, UK.
I
I
Basnak
M
M
Sun
T A
TA
Hamor
F
F
Focher
A
A
Verri
S
S
Spadari
B
B
Wroblowski
P
P
Herdewijn
R T
RT
Walker
D000998:Antiviral Agents / Q000138:chemical synthesis; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D001380:Azauridine / Q000031:analogs & derivatives*; D001792:Blood Platelets / Q000201:enzymology; D018360:Crystallography, X-Ray; D003857:Deoxyuridine / Q000031:analogs & derivatives*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis; D006561:Herpes Simplex / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D009705:Nucleosides / Q000138:chemical synthesis / Q000494:pharmacology; D010766:Phosphorylation; D013936:Thymidine / Q000378:metabolism; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors
D000998:Antiviral Agents; D001372:Aza Compounds; D004791:Enzyme Inhibitors; D009705:Nucleosides; D001380:Azauridine; D013937:Thymidine Kinase; D013936:Thymidine; D003857:Deoxyuridine