Excellence
Viral infections: molecular insights, targets for intervention and drug development
| Coordinator | Jan Balzarini |
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| Centre |
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Research area
Pathogen (including viral) infections are responsible for a high incidence of morbidity, mortality and economic losses. Antiviral chemotherapeutics are either not available, or have often a limited use due to long−term side effects and/or eventual drug resistance development. Within the current therapeutic targets virus entry and transmission are still under−represented. The major efforts (including ours) have for a long time been focused on other valuable targets such as virus−encoded reverse transcriptase/DNA polymerases and HIV protease, and related issues on drug resistance development. A limited amount of efforts were devoted to (co)receptors of HIV. This research will now be put in a broader context of virus entry. A better understanding of the complex process of virus entry and transmission will allow a more rational development of antiviral drugs.
Expertise
Research is focused on the discovery, design and development of new drug leads (nucleoside analogues, acyclic nucleoside phosphonates, non-nucleoside analogues) in antiviral and anticancer chemotherapy. Mechanism of action and structure-activity relationship studies, including elucidation of target enzyme/protein-drug interaction, metabolic pathways (pharmacology) and drug resistance development are performed. A broad compound screening/drug discovery programme against a wide variety of viruses and cancer cells is also in place.
Approach
Our major objectives are (i) to discover novel drug leads and to define therapeutic concepts for antiviral chemotherapy with the aim to develop at least one drug and/or one novel therapeutic concept that has the potential to further proceed to clinical studies, (ii) to obtain new fundamental insights in the interaction of Lactobacillus bacteria (beneficial members of the microbiota) with virus infection, immune cells and antiviral drugs, (iii) to establish new 3D skin model/3D−raft cultures (OERC) and novel relevant virus infection models in the OERC and in mice that will allow to gain more insights in the drug effects and role of cells from the innate immunity on the virus infection and associated pathology, (iv) to gain new molecular insights in the mechanisms of drug action and (v) to establish a glycoprotein expertise platform within the PF Consortium. In terms of biological agents, we will investigate novel carbohydrate−binding agents (CBAs), either peptidic or non−peptidic, virus (co)−receptor antagonists/immune cell modulators, and acyclic nucleoside phosphonates (ANPs), on their antiviral activity and molecular mechanism of action. In terms of therapy, we want to succeed in expressing the gene of the most interesting CBAs in Lactobacillus sp. as a potential microbicidal approach to prevent HIV infection/transmission and to establish new 3D (OERC)/in vivo (mice) models for investigating/validating the drug action and elucidating their effects on virus pathogenicity.
We estimate that the proposed PF−Program will generate important new insights in drug action and the effect of novel drugs on viral pathology which will generate new therapeutic concepts to treat lethal virus infections.