N-ribohydrolases as activators of prodrugs

Both research teams will join forces to design inactive non-toxic prodrugs that can be hydrolysed specifically into ribose and a toxic (parasiticidal) product by particular bacterial or parasitic N-ribohydrolases. The choice for bacterial and parasitic N-ribohdrolases, a family of enzymes that has no representatives within mammals, as generic prodrug activating enzymes opens the way to two different prodrug strategies, leading to different therapeutic applications.
The first prodrug strategy consists of killing particular bacteria or parasites by systemic cytotoxic compounds that are selectively activated by the parasite's N-ribohydrolase. By including the hyrolases of the genera Campylobacter, Escherichia, Staphylococcus, Trypanosoma, Plasmodium, Leishmania, Pseudomonas, Mycobacterium, and Toxoplasma, we aim to discover a number of new lead compounds that can be developed and validated for the treatment food poisoning and opportunistic infections and against (neglected) infectious diseases including malaria, tuberculosis, sleeping sickness, Chagas disease, and Leishmaniasis.
Our second prodrug strategy is based on delivery techniques and includes the activation of non toxic compounds by exogenous ribohydrolases that are targeted to a particular cell type. In this part of the program, we would like to validate gated Self-Assembling NanoStructures (SONS) filled with ribohydrolases as nanoreactors to activate particular prodrugs 'in situ'. To deliver these SONS to particular cells, specific single domain antibodies will be fused to theses nanoparticles by chemical or biochemical means.