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PLoS Negl Trop Dis. 2015 Oct 20;9(10):e0004132. doi: 10.1371/journal.pntd.0004132. eCollection 2015.

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

Author information

1
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.
2
Institute of Cell Biology and Neurobiology, CNR, Rome, Italy.
3
Institute of Chemical Methodologies, CNR, Rome, Italy.
4
Departments of Biochemistry, the University of Texas Health Science Center, San Antonio, Texas, United States of America.
5
Departments of Biochemistry, the University of Texas Health Science Center, San Antonio, Texas, United States of America; Department of Pathology, the University of Texas Health Science Center, San Antonio, Texas, United States of America.
6
Texas Biomedical Research Institute, San Antonio, Texas, United States of America.
7
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; Department of Veterans Affairs, South Texas Veterans Health Care System, San Antonio, Texas, United States of America.

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.

PMID:
26485649
PMCID:
PMC4618941
DOI:
10.1371/journal.pntd.0004132
[Indexed for MEDLINE]
Free PMC Article

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