Selective antiherpetic activity of carbocyclic analogues of (E)-5-(2-halogenovinyl)-2'-deoxyuridines: dependence on specific phosphorylation by viral thymidine kinase.
The carbocyclic analogues of (E)-5-(2-bromovinyl)-2'-deoxyuridine (C-BVDU) and (E)-5-(2-iodovinyl)-2'-deoxyuridine (C-IVDU), in which the sugar moiety is replaced by a cyclopentane ring, are as efficient substrates for the herpes simplex type 1 (HSV-1)-encoded thymidine kinase (TK) as their parent compounds (BVDU and IVDU). This conclusion is based on the binding affinities (Ki) of BVDU, IVDU, C-BVDU and C-IVDU to the HSV-1 TK and on the phosphorylation rates (Km, Vmax) of (125I)IVDU and (125I)C-IVDU by the enzyme. The specific phosphorylation of C-BVDU and C-IVDU by the viral TK may explain why these compounds are highly selective inhibitors of HSV-1 replication.
De Clercq
E
E
Balzarini
J
J
Bernaerts
R
R
Herdewijn
P
P
Verbruggen
A
A
D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism*; D001973:Bromodeoxyuridine / Q000031:analogs & derivatives* / Q000378:metabolism; D007065:Idoxuridine / Q000031:analogs & derivatives* / Q000378:metabolism; D007668:Kidney; D007700:Kinetics; D010766:Phosphorylation; D011817:Rabbits; D018139:Simplexvirus / Q000201:enzymology*; D013937:Thymidine Kinase / Q000378:metabolism*
D000998:Antiviral Agents; C020235:brivudine; C030360:5-(2-iodovinyl)-2'-deoxyuridine; D013937:Thymidine Kinase; D001973:Bromodeoxyuridine; D007065:Idoxuridine