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

Publication Type:

Journal Article

Source:

PLoS Negl Trop Dis, Volume 9, Issue 10, p.e0004132 (2015)

Keywords:

Animals, Anthelmintics, Chromatography, Crystallography, X-Ray, Female, Mice, Models, Molecular, Oxamniquine, Parasitic Sensitivity Tests, Protein Binding, Protein Conformation, Schistosoma mansoni, Stereoisomerism, Sulfotransferases

Abstract:

<p><b>BACKGROUND: </b>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.</p><p><b>METHODOLOGY/PRINCIPAL FINDINGS: </b>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.</p><p><b>CONCLUSIONS/SIGNIFICANCE: </b>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.</p>

Detector: 
Q315