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9-(2-Hydroxypropyl)adenine: A Novel Fraudulent Substrate of HSV1-Thymidine Kinase. An Interdisciplinary Study
1 , 2 , 3 , 2 , 1 , 1 , 1 , * 1
1  Department of Pharmacy, ETH Zürich, Winterthurerstrasse 190, 8057 Zürich
2  Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulicev 19, 10000 Zagreb
3  Pliva Research Institute, Prilaz Baruna Filipovica 25, 10000 Zagreb

Abstract: Herpes Simplex virus type 1 thymidine kinase (HSV1 TK) phosphorylates thymidine (dT) to thymidine monophosphate (dTMP) playing a key role in reactivation from the latency and replication of herpes simplex viruses. Acyclovir (ACV) and gancyclovir (GCV) are today the only therapeutic compounds to interfere with a severe HSV infection. Those molecules act as fraudulent substrates blocking virus proliferation by dead end complexes with the viral DNA after being activated by the HSV-specific TK. Furthermore, HSV1 TK was more recently used as a suicide enzyme in gene therapy of cancer (1,2) and AIDS (3) in combination with ACV. The molecular basis of the selective therapy, that uses HSV1 TK as target, is the difference in substrate specificity between the human cellular and the herpesviral TK isoenzymes. Because of the important therapeutic implications, HSV is not only linked to viral infection but also with other diseases such as Kaposi's Sarcoma (4) and Alzheimer disease (5), and the increase of resistance towards ACV and GCV, intensive efforts have been directed towards the search of new compounds with general antiviral activity (6). In this study we report the results of a first cycle of structure-based drug-design aiming the development of new compounds for antiviral and gene therapy.
Keywords: n/a