Structural and functional characterization of the enantiomers of the antischistosomal drug oxamniquine.

Author Summary:

Schistosomes, parasites that cause the disease schistosomiasis in humans, are blood flukes that infect an estimated 200 million people in 76 countries. Control of schistosomiasis is currently based on repeated doses of the drug praziquantel (PZQ). Parasites showing reduced susceptibility to PZQ have been recovered from patients that failed PZQ treatment and have been obtained by experimental selection. New anti-schistosomal drugs are therefore needed that can be used with PZQ to minimize the probability of resistance. The older anti-schistosomal drug oxamniquine (OXA) has an excellent efficacy and safety record but is only active against one of the three species infecting humans. Recently, a combination of genetic and structural analyses resulted in the determination of the structure of OXA in complex with its target enzyme in the parasite, providing opportunity for structure-guided modifications of OXA to make it more effective against all three schistosome species. Synthesis of OXA results in a racemic mixture. Here, we isolate OXA enantiomers and find that one is more effective than the other at killing schistosomes. Crystal structures of both OXA enantiomers bound to the target enzyme suggest a molecular basis for this observation that should be considered in ongoing and future OXA-based drug design efforts.

CONCLUSIONS/SIGNIFICANCE: Together the data suggest the higher schistosomicidal activity of S-OXA is correlated with its ability to outcompete R-OXA binding the sulfotransferase active site. These findings have important implications for the design, syntheses, and dosing of new OXA-based antischistosomal compounds.