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Drug discovery for schistosomiasis
Schistosomiasis treatment relies on a single drug - praziquantel - that was discovered in the 1970's. The use of just one drug to control this disease is concerning because of (i) the potential for resistance, which can be reproducibly selected in the lab and has been reported in veterinary flatworm parasites, and (ii) the fact that a subset of human infections do not respond to praziquantel treatment even after repeated dosing.
One barrier to designing alternative anti-schistosomal drugs with unique mechanisms is that we have a poor understanding of how praziquantel and other existing anthelmintics actually work. Therefore, our lab's work has two broad goals:
1. Understand existing anthelmintics' MoA.
1. Understand existing anthelmintics' MoA.
Praziquantel's mechanism of action (MoA) is poorly understood despite >40 years of research. However, the drug likely requires engagement of the host immune system to clear parasite infections.
The role of the immune system is interesting, because this focus on host-parasite interaction raises the larger question of how worms evade the immune recognition for years (even decades) while living in the bloodstream among the milieu of host immune cells.
This work is outlined in more detail in the preprint below.
2. Identify new anti-parasitic leads.
2. Identify new anti-parasitic leads.
By understanding how existing anthelmintics work, we will be able to design more productive assays that can be employed for novel drug screens.
One series that we are following up on is based on the benzodiazepine meclonazepam (above), which was effective in human trials but halted in the 1980's due to dose-limiting sedation. Benzodiazepine SAR is now better understood, and it is clear that analogs can be generated with far less side effects.
This work was recently published in PLoS Neglected Tropical Diseases and can be found below.
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