engleski

Adenine with acyclic side chain acts as fraudulent substrate of HSV1 thymidine kinase

HSV1 TK (Herpes Simplex Virus1 Thymidine Kinase) plays a key role in the replication of herpes simplex viruses. Acyclovir and gancyclovir are today the only therapeutic compounds to interfere with a severe HSV infection. The broad use of this type of anti-herpetica even in cases of non-severe infection is the reason of tremedous increase of resistance and therefore of severe problem for the treatment. Thus intensive efforts have been directed towards the search of new compounds with general antiviral activity. With this aim a novel class of acyclic adenine nucleoside /1/ has been prepared. To test if the new compounds would theoretically interact with HSV1-TK, whose structure is known /2/, the molecular modeling program DOCK has been used. The results of the docking, suggested that 9-(2-hydroxypropyl)adenine (9-HPA) could possibly be a fraudulent substrate of TK. To verify this prediction, kinetics as well as analytical studies have been undertaken. The results of monitoring the phosphorylation of substrates by TK, using UV-spectrophotometry as well as HPLC, indicate that 9-HPA is indeed phosphorylated by the enzyme and confirm prediction. Thus, 9-(2-hydroxypropyl)adenine is indeed a novel fraudulent substrate of HSV1 and may be a useful lead compound for structure-based drug design of more potent therapeutic compounds

adenine; acyclonucleosides; fraudulent substrate of HSV1 thymidine kinase

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