5BYJ

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

(2015) PLoS Negl Trop Dis 9: e0004132-e0004132

• PubMed: 26485649 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1371/journal.pntd.0004132
• Primary Citation of Related Structures:  
  5BYJ, 5BYK


• PubMed Abstract: 
  

  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. 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. 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.

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Organizational Affiliation: 

Departments of Biochemistry, the University of Texas Health Science Center, San Antonio, Texas, United States of America; X-ray Crystallography Core Laboratory, the University of Texas Health Science Center, San Antonio, Texas, United States of America.