L-Thymidine is phosphorylated by herpes simplex virus type 1 thymidine kinase and inhibits viral growth
| Autor: | S, Spadari, G, Maga, F, Focher, G, Ciarrocchi, R, Manservigi, F, Arcamone, M, Capobianco, A, Carcuro, F, Colonna, S, Iotti |
|---|---|
| Rok vydání: | 1992 |
| Předmět: |
Cell Survival
Deoxyribonucleosides medicine.disease_cause Thymidine Kinase Virus HeLa chemistry.chemical_compound Leucine Drug Discovery medicine Humans Simplexvirus Uridine chemistry.chemical_classification biology Chemistry Cell growth Stereoisomerism biology.organism_classification Molecular biology In vitro Enzyme Herpes simplex virus Biochemistry Thymidine kinase Molecular Medicine Thymidine Cell Division HeLa Cells |
| Zdroj: | Journal of Medicinal Chemistry. 35:4214-4220 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00100a029 |
| Popis: | We have demonstrated that herpes simplex 1 (HSV1) thymidine kinase (TK) shows no stereospecificity for D- and L-beta-nucleosides. In vitro, L enantiomers are not recognized by human TK, but function as specific substrates for the viral enzyme in the order: L-thymidine (L-T) >> 2'-deoxy-L-guanosine (L-dG) > 2'-deoxy-L-uridine (L-dU) > 2'-deoxy-L-cytidine (L-dC) > 2'-deoxy- L-adenosine (L-dA). HSV1 TK phosphorylates both thymidine enantiomers to their corresponding monophosphates with identical efficiency and the Ki of L-T (2 microM) is almost identical to the Km for the natural substrate D-T (2.8 microM). The L enantiomer reduces the incorporation of exogenous [3H]T into cellular DNA in HeLa TK-/HSV1 TK+ but not in wild-type HeLa cells, without affecting RNA, protein synthesis, cell growth, and viability. L-T markedly reduces HSV1 multiplication in HeLa cells. Our observations could lead to the development of a novel class of antiviral drugs characterized by low toxicity. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|