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

Alexander B. Taylor, Livia Pica-Mattoccia, Chiara M. Polcaro, Enrica Donati, Xiaohang Cao, Annalisa Basso, Alessandra Guidi, Anastasia R. Rugel, Stephen P. Holloway, Timothy J.C. Anderson, P. John Hart, Donato Cioli, Philip T. LoVerde

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere0004132
JournalPLoS Neglected Tropical Diseases
Volume9
Issue number10
DOIs
StatePublished - Oct 20 2015

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Infectious Diseases

Fingerprint Dive into the research topics of 'Structural and Functional Characterization of the Enantiomers of the Antischistosomal Drug Oxamniquine'. Together they form a unique fingerprint.

Cite this