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by zope1 — last modified 2006-01-16 15:19

VIRGIL-DRUGPHARM

The VIRGIL-DRUGPHARM platform develops a completely unmet need, i.e. a pharmacological approach of viral drug resistance, particularly in the field of influenza and viral hepatitis. Indeed, the major objective of this platform is to determine the influence of pharmacokinetics and intracellular pharmacology in the development of antiviral drug resistance. To that end, it combines the activities of European scientists that are leaders in medicinal chemistry (more in particular of antivirals) and peptide synthesis.

Antivirals drugs can roughly be divided into two main classes, i.e. nucleoside analogues and non-nucleosides. Therfore, resources have been integrated in this platform to be capable of synthesizing nucleoside analogues and, importantly also the 5�-triphosphate metabolites, which are required when directly studying the effect of the drugs at the enzymatic level in cell free systems, as well as non-nucleoside analogues. This provides the capacity of new drug synthesis to make them available to the other VIRGIL platforms for mechanistic studies. Furthermore, VIRGIL-DRUGPHARM creats a core facility for the design of the appropriate detection methods (pharmacokinetic assays) and for molecular modelling. This latter technology is important to further help to understand at the molecular level how drugs may interact with the viral or cellular molecular target. A second task is to study the intracellular pharmacology of drugs. Indeed, a very important issue in understanding mechanisms of drug resistance, as well as how to rationally design drug-combinations, is to obtain insight in the intracellular pharmacology of such molecules. For nucleoside analogues this relates mainly to the intracellular phosphorylation. A final task is to design strategies to avoid the emergence of drug resistance or to allow treating drug resistant viruses by increasing their sensitivity to the existing drug by modulating the host cell metabolism (in collaboration with VIRGIL-HOST).

The joint effort results in an efficient centralized facility that serves most of the other VIRGIL platforms. It allows novel insights in how possible altered pharmacokinetics of antiviral drugs may contribute to the insensitivity of certain patients to therapy or to a faster selection of drug resistant strains, which leads to formulation of novel standards when dissecting which factors contribute to drug-resistance in particular cohorts, and ultimately promotes tailored treatments. This also provides strategies to prevent the emergence of drug resistance against nucleoside analogues by modulating the metabolism of the host cell.

In summary, VIRGIL-DRUGPHARM provides to the entire network a core facility:

	for the synthesis of small molecules and peptides, otherwise not available to the consortium
	for molecular modelling of interactions between drugs and wild-type or drug-resistant viral targets,
	for designing sensitive pharmacokinetic assays,
	to study the intracellular metabolism of drugs (either alone or combined)
	for preliminary toxicity studies in animals.

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