Structural and Functional Characterization of the Enantiomers of the Antischistosomal Drug Oxamniquine

Background: for over two decades,a racemic mixture of oxamniquine (oxa) was administered to patients infected by schistosoma mansoni,but whether one or both enantiomers exert antischistosomal activity was unknown. recently,a ~30 kda s. mansoni sulfotransferase (smsult) was identified as the target of oxa action. methodology/principal findings: here,we separate the oxa enantiomers using chromatographic methods and assign their optical activities as dextrorotary [(+)-oxa] or levorotary [(-)-oxa]. crystal structures of the parasite enzyme in complex with optically pure (+)-oxa and (-)-oxa) reveal their absolute configurations as s- and r-,respectively. when tested in vitro,s-oxa demonstrated the bulk of schistosomicidal activity,while r-oxa had antischistosomal effects when present at relatively high concentrations. crystal structures r-oxa•smsult and s-oxa•smsult complexes reveal similarities in the modes of oxa binding,but only the s-oxa enantiomer is observed in the structure of the enzyme exposed to racemic oxa. 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. © 2015 taylor et al.