Viral infections: molecular insights, targets for intervention and drug development

Pathogen (including viral) infections are responsible for a high incif morbidity, mortality and economic losses. Antiviral chemotherapeutics her not available, or have often a limited use due to long-term side effd/or eventual drug resistance development. Within the current thic targets virus entry and transmission are still under-represented. Thenbsp;efforts (including ours) have for a long time been focused on otherle targets such as virus-encoded reverse transcriptase/DNA polymerases anbsp;protease, and related issues on drug resistance development. A limiunt of efforts were devoted to (co)receptors of HIV. This research will put in a broader context of virus entry. A better understanding of the cprocess of virus entry and transmission will allow a more rational develof antiviral drugs. In this proposal we will inve the interaction of novel drug leads against virus entry and transm(i.e. human immunodeficiency virus (HIV), Dengue virus (DENV)) thereby f on both partners of the interaction: the viral (envelope) and the celluo)-receptor) perspective. Importantly, we wil also focuss on the naturalrships of the host with its microscopic residents (the microbiota) tential means for the prevention of virus transmission and cell entry byENV and enterovirus. Given the importance of the microbiota in overall hwe will also investigate on how the (newly designed) chemotherapeutics aepresentatives of the microbiota and the immune system. The latter s important from a microbicidal (i.e. HIV) perspective. Our 3-dimensionaotypic epithelial raft culture (OERC) technology that has been developeditheliotropic virus infections such as papilloma-, herpes-, and pox, will now be adapted to the virus infections subject of the currencation. It will allow to study the role of immune cells and the impinvestigational new drug leads on the virus infection and pathology.bsp; Our major objectives are (i) to discover novel drug leads and to define therapeutic s for antiviral chemotherapy with the aim to develop at least one d/or one novel therapeutic concept that has the potential to further procclinical studies, (ii) in new fundamental insights in the interaction of Lactobacem> bacteria (beneficial members of the microbiota) with virus infeimmune cells and antiviral drugs, (iv) to gain new molecular insights inchanisms of drug action and (v) to establish a glycoprotein expertised platform within the PF Consorti In terms of biological agents, we will investigate novel carbohydrate-binding agents (CBAs), either peptidic or non-peptidic, viruseceptor antagonists/immune cell modulators, and acyclic nucleoside phosp (ANPs), on their antiviral activity and molecular mechanism of action. s of therapy, we want to succeed in expressing the gene of the most inte CBAs in Lactobacillus sp. as a potential microbicidal appo prevent HIV infection/transmission and to establish new 3D (OERC)/ (mice) models for investigating/validating the drug action and elug their effects on virus pathogenicity. The generf profound insights in the viral pathways and mechanisms of drug ree development will be one of our major tasks, because they will contribunderstanding the mechanisms of drug action, and enable anticipating potential clinical value of the compounds. We estimate that theed PF-Program will generate important new insights in drug action and tht of novel drugs on viral pathology which will generate new therapencepts to treat lethal virus infections.

Keywords:Viral infections

Disciplines:Microbiology, Systems biology, Laboratory medicine