Laboratory of Virology and Chemotherapy (Rega Institute)
This unit designs and develops antiviral and antitumor agents, primarily nucleoside, nucleotide or oligonucleotide analogues but also other substances which interact with enzymes involved in nucleic acid metabolism (i.e. DNA polymerase, reverse transcriptase, thymidine kinase, thymidylate kinase, nucleoside phosphorylase, dihydropyrimidine dehydrogenase, adenosine deaminase, S-adenosylhomocysteine hydrolase, IMP dehydrogenase, OMP decarboxylase, CTP synthetase, etc.), as well as compounds which interact with other processes such as virus binding to the cells, virus-cell fusion (i.e. interaction of HIV with chemokinereceptors such as CXCR4 and CCR5), proviralDNA integration, trans-acting transactivator (TAT)-mediated transcription, angiogenesis, apoptosis, cell differentiation. Particular efforts are directed towards the developmnet of potent and selective inhibitors of the human immunodeficiency virus (HIV, the etiologic agent of AIDS) and other important viral pathogens such as herpes simplex virus (HSV), varicella- zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), human papilloma virus (HPV), adeno-, entero-, toga-, flavi-, orthomyxo-, paramyxo-, arena-, rhabdo- and reoviruses. The strategies pursued in the development of anti-cancer agents are based on angiogenesis inhibitors, tumor cell differentiation inducers, apoptosis inducers and combined gene/chemotherapy (following transfection of the tumor cells with the HSV-1, HSV-2 or VZV thymidine kinase ge ne). Research is focused on the identification of the molecules, e.g. enzymes,receptor proteins or molecular processes, where the chemotherapeutic agents have to be targeted to achieve optimal antiviral and/or antitumor effects. Various cellular and animal model systems have been developed for the biological evalu ation of the compounds. A broad range of biochemical, cytometric, biomolecularand analytical procedures are employed for the exploration of the mode of action of the antiviral and antitumor agents. Advanced technology includes FACS, HPLC, BiaCore, DNA sequencing, and a software program for the automated evaluation of anti-HIV activity. Using these approaches, several compounds have been developed that are now licensed for clinical use (i.e. stavudine for the treatmentof AIDS, cidofovir for the treatment of CMV retinitis in AIDS patients) or have been subject of advanced (phase III) clinical trials (i.e. brivudin (BVBV) for the treatment of VZV infections, loviride (alfa-APA) for the treatment of AIDS, adefovir dipivoxil (bis(PDM)-PMEA) for the treatment of AIDS and hepatitis mm B) Other compounds discovered in our unit (i.e. (bis(PDC)-PMPA, MKC-442 (I-EBU) and the bicyclams) have recently entered clinical trials (phase III and I-EBU, and phase I for bicyclam AMD 3100) in the prevention and/or therapy of HIV infections.