%0 Journal Article
%T Structural and Functional Characterization of the Enantiomers of the Antischistosomal Drug Oxamniquine
%A Alessandra Guidi
%A Alexander B. Taylor
%A Anastasia R. Rugel
%A Annalisa Basso
%A Chiara M. Polcaro
%A Donato Cioli
%A Enrica Donati
%A Livia Pica-Mattoccia
%A P. John Hart
%A Philip T. LoVerde
%A Stephen P. Holloway
%A Timothy J. C. Anderson
%A Xiaohang Cao
%J -
%D 2015
%R 10.1371/journal.pntd.0004132
%X 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
%K Enantiomers
%K Crystal structure
%K Schistosoma mansoni
%K High performance liquid chromatography
%K Schistosoma
%K Hydrogen bonding
%K Enzyme structure
%K Parasitic diseases
%U https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0004132