Nanobodies as chaperones to study Biomedical Targets

Matching project: Nucleoside hydrolases: from salvage enzymes to generic prodrug targets.
The NH's are widely distributed in bacteria, protozoa, fungi, plants and insects but they are conspicuously absent in mammals. The lack of NH activity in man makes thes enzymes attractive targets for antiparasitic drug design. Nearly all parasitic protozoa lack a de novo purine biosynthesis pathway and the NH's catalyse the first step of their only metabolic alternative: the purine salvage pathway.

In the following years our research team aims at validating the family of nucleoside hydrolases as generic targets for therapeutic pro-drugs. We want to develop inactive non-toxic pro-drugs that can be hydrolysed specifically into ribose and a toxic (bactericidal or parasiticidal) product by particular bacterial or parasitic nucleoside hydrolases. Apart from there use as anti-parasitic compounds, these pro-drugs also have potential in cancer chemotherapy. Exogenous NH's can be targeted specifically to tumour sites (e.g. ADEPT or GDEPT strategies) where they would activate in situ a systemically administered pro-drugs. A thorough understanding of the mechanism and structure-function relationship of the involved enzymes is an absolute prerequisite for the rational and efficient development of such a pro-drug design programme. The current project therefor aims at studying a number of fundamental aspects of the nucleoside hydrolases.