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• Study of human and viral enzymes involved in the biosynthesis of nucleotides for the development of nucleoside and non-nucleoside compounds with antineoplastic and antiviral activity


Federico Focher

The identification of novel compounds with potential antineoplastic and antiviral activity is a multistep process which comprehends:

•    identification of molecular targets (target selection)
•    selection of molecules interfering with the target function (screening)
•    demonstration of the biological effect when the target function is inhibited (target validation)
•    Selection of a molecule with maximal specific activity and minimal aspecific toxicity (lead identification)

Through an integrated approach, our group is able to perform all these steps, from the target selection to the lead identification.

Our studies in the field of the Enzymology of DNA and Molecular Virology focus on: 1) cloning, expression, purification and biochemical characterization of enzymes involved in the metabolization (anabolic and catabolic) of nucleoside and nucleotides analogs with potential anticancer and antiviral activity (nucleoside kinases, phosphorylases, DNA polymerases, etc.); and 2) in vitro and in vivo (cell cultures) characterization of natural and synthetic compounds, specifically acting against human and viral enzymes, with potential anticancer and antiviral (HSV, HCV, etc.) activity.

In particular we have cloned and expressed in E. coli the human angiogenic factor PD-ECGF, or thymidine phosphorylase (TP), deoxycytidine kinase (dCK), adenosine kinase (AK), uridine-cytdine kinase (UCK), purine nucleosidephosphorylase (hPNP), human and herpetic thymidine kinase (TK), etc.
Our studies allowed a detailed knowledge of the active site of the enzymes under investigation and the discovery and patent of several molecules interfering with cell and viral proliferation.
Study in progress: mechanism of action of some non-nucleoside compounds active against human Adenosine kinase.

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