Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.1.21 (thymidine kinase)
 7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

9-[4-Hydroxy-3-(hydroxymethyl)butyl]guanine (3HM-HBG), (RS)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine ([+/-]2HM-HBG), and cis-9-(4-hydroxy-2-butenyl)guanine (2EN-HBG), new acyclic guanosine analogs structurally related to buciclovir (BCV [(R)-9-(3,4-dihydroxybutyl)guanine]), were evaluated in parallel with buciclovir as anti-herpes simplex virus (HSV) agents. In cell cultures, replication of different strains of HSV type 1 (HSV-1) and HSV-2 was inhibited at nontoxic drug concentrations. The concentrations giving 50% inhibition of plaque formation were, however, dependent on virus strain and cell type. In most cell types, the order of activity against HSV-1 strains was 3HM-HBG greater than (+/-)2HM-HBG greater than BCV greater than 2EN-HBG, whereas the drugs showed an approximately equivalent activity against HSV-2 strains in different cells. The cytotoxic effects of the drugs were also cell type dependent, the order of activity being BCV greater than 3HM-HBG = (+/-)2HM-HBG greater than 2EN-HBG. At growth-inhibitory concentrations, the guanosine analogs BCV, 3HM-HBG, and (+/-)2HM-HBG showed clastogenic effects in human lymphocytes, mainly because of the induction of chromatid breaks. When evaluated for their anti-HSV effects in systemic HSV-1 infections in mice, the order of activity was BCV = 3HM-HBG greater than (+/-)2HM-HBG greater than 2EN-HBG, and in mice infected systemically with HSV-2, only BCV and 3HM-HBG showed efficacy. The differences between efficacy in vitro and in vivo could be explained in part by differences in kinetics of the drugs in mouse plasma, as the more efficacious drugs, BCV and 3HM-HBG, showed lower clearances and longer half-lives than the less efficacious ones, (+/-)2HM-HBG and 2EN-HBG. When used topically against a cutaneous HSV-1 infection in guinea pigs, 3HM-HBG showed an effect equivalent to that of BCV, whereas (+/-)2HM-HBG and 2EN-HBG were inactive. Mechanistically, the guanosine analogs were characterized by a high affinity for the viral thymidine kinase and a low affinity fo a cellular thymidine kinase and by their inhibition of viral DNA synthesis in infected cells.
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PMID:Mode of action, toxicity, pharmacokinetics, and efficacy of some new antiherpesvirus guanosine analogs related to buciclovir. 302 62

The antiviral activity of five structurally related pyrimidine nucleosides, E-5-propenyl-2'-deoxyuridine, 5-allyl-2'-deoxyuridine, E-5-(1-butenyl)-2'-deoxyuridine, 5-(2-butenyl)-2'-deoxyuridine, and 5-butyl-2'-deoxyuridine, in cell culture against herpes simplex virus type 1 was examined. Analogs in which the C-C double bond of the 5-substituent was in conjugation with the pyrimidine ring were more potent antiviral drugs than were the corresponding nonconjugated and alkyl-substituted analogs. Differences in antiviral activity similar to those observed in cell culture occurred in virus-infected mice. The molecular basis for the greater antiviral activity of the conjugated isomers was investigated. It was observed that the conjugated isomer E-5-propenyl-2'-deoxyuridine had a greater affinity for virus thymidine kinase and, as the 5'-triphosphate, for virus DNA polymerase than did the nonconjugated isomer 5-allyl-2'-deoxyuridine. The results are discussed in relation to other data in the literature.
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PMID:Possible molecular basis for antiviral activity of certain 5-substituted deoxyuridines. 630 12

Two series of analogues of the novel human mitochondrial thymidine kinase inhibitor 1-[(Z)-4-(triphenylmethoxy)-2-butenyl]thymine were synthesized by replacing the triphenylmethoxy moiety by a variety of substituted amines and carboxamides. In all the cases, the selectivity against the mitochondrial enzyme was either maintained or improved, and several derivatives were almost as potent as the parent compound. A molecular model was built that can account for the observed selectivities.
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PMID:Improving the selectivity of acyclic nucleoside analogues as inhibitors of human mitochondrial thymidine kinase: replacement of a triphenylmethoxy moiety with substituted amines and carboxamides. 1294 26

Mitochondrial thymidine kinase or TK-2 belongs to the family of mammalian deoxynucleoside kinases (dNKs) that catalyze the phosphorylation of deoxynucleosides to their corresponding deoxynucleoside monophosphates by gamma-phosphoryl transfer of ATP. These enzymes are instrumental in the activation of deoxynucleoside analogues with biological and therapeutic properties. Moreover, dNKs are fundamental to maintain dNTPs pools for DNA synthesis and repair. TK-2 has a mitochondrial localization and is the only thymidine kinase that is physiologically active in non-proliferating and resting cells. Several recent investigations point to an important role of TK-2 in the maintenance of mitochondrial dNTPs pools. Indeed, mutations in the gene encoding TK-2 have been associated with mitochondrial DNA (mtDNA) depletion that mostly affects skeletal muscle. Moreover, TK-2 has been suggested to be implicated in mitochondrial toxicity associated to prolonged treatments with nucleoside analogues (i.e AZT for the treatment of AIDS patients). In this scenario, TK-2 inhibitors could be a useful tool to further clarify both the physiological role of TK-2 in the maintenance of mitochondrial dNTP pools, and the possible contribution of TK-2 to the mitochondrial toxicity of pyrimidine nucleoside analogues. In the present article we review the most recent literature covering different aspects of TK-2 as well as published TK-2 inhibitors, with special emphasis on acyclic nucleoside analogues that have been described by our research groups and whose prototype compound is 1-[(Z)-4-(triphenylmethoxy)-2-butenyl]thymine.
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PMID:Mitochondrial thymidine kinase inhibitors. 1630 27

Novel N1-substituted thymine derivatives related to 1-[(Z)-4-(triphenylmethoxy)-2-butenyl]thymine have been synthesized and evaluated against thymidine kinase-2 (TK-2) and related nucleoside kinases [i.e., Drosophila melanogaster deoxynucleoside kinase (Dm-dNK) and herpes simplex virus type 1 thymidine kinase (HSV-1 TK)]. The thymine base has been tethered to a distal triphenylmethoxy moiety through a polymethylene chain (n = 3-8) or through a (2-ethoxy)ethyl spacer. Moreover, substitutions at position 4 of one of the phenyl rings of the triphenylmethoxy moiety have been performed. Compounds with a hexamethylene spacer (18, 26b, 31) displayed the highest inhibitory values against TK-2 (IC50 = 0.3-0.5 microM). Compound 26b competitively inhibited TK-2 with respect to thymidine and uncompetitively with respect to ATP. A rationale for the biological data was provided by docking some representative inhibitors into a homology-based model of human TK-2. Moreover, two of the most potent TK-2 inhibitors (18 and 26b) that also inhibit HSV-1 TK were able to reverse the cytostatic activity of 1-(beta-D-arabinofuranosyl)thymine (Ara-T) and ganciclovir in HSV-1 TK-expressing OST-TK-/HSV-1 TK+ cell cultures.
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PMID:N1-substituted thymine derivatives as mitochondrial thymidine kinase (TK-2) inhibitors. 1718 Nov 58