Structural and Functional Characterization of the Enantiomers of the Antischistosomal Drug Oxamniquine: e0004132

• Published in: PLoS neglected tropical diseases 2015-10, Vol.9 (10)
• Main Authors: Taylor, Alexander B, Pica-Mattoccia, Livia, Polcaro, Chiara M, Donati, Enrica, Cao, Xiaohang, Basso, Annalisa, Guidi, Alessandra, Rugel, Anastasia R, Holloway, Stephen P, Anderson, Timothy JC, Hart, P John, Cioli, Donato, LoVerde, Philip T
• Format: Article
• Language: English
• Subjects: Collaboration; Enzymes; Laboratories; Parasites; Tropical diseases; Worms
• ISSN: 1935-2727; 1935-2735
• DOI: 10.1371/journal.pntd.0004132

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[bullet]SmSULT and S-OXA[bullet]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.