TY - JOUR
T1 - Structural and Functional Characterization of the Enantiomers of the Antischistosomal Drug Oxamniquine
AU - Taylor, Alexander B.
AU - Pica-Mattoccia, Livia
AU - Polcaro, Chiara M.
AU - Donati, Enrica
AU - Cao, Xiaohang
AU - Basso, Annalisa
AU - Guidi, Alessandra
AU - Rugel, Anastasia R.
AU - Holloway, Stephen P.
AU - Anderson, Timothy J.C.
AU - Hart, P. John
AU - Cioli, Donato
AU - LoVerde, Philip T.
N1 - Funding Information:
Funding: This research was supported by NIH grant 1R01AI115691 (PTL and PJH), WHO grant HQNTD1206356 (PTL), the UTHSCSA Presidents Collaborative Research Fund (PTL and PJH), and the Robert A. Welch Foundation (AQ-1399, PJH) Support for the X-ray Crystallography Core Laboratory by the
Funding Information:
UTHSCSA Office of the Vice President for Research is gratefully acknowledged. This work is based upon research conducted at the Northeastern Collaborative Access Team beamlines, which are funded by the National Institute of General Medical Sciences from the National Institutes of Health (P41 GM103403). The Pilatus 6M detector on 24-ID-C beam line is funded by a NIH-ORIP HEI grant (S10 RR029205). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. ARR was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant TL1 TR001119. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
PY - 2015/10/20
Y1 - 2015/10/20
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pntd.0004132
DO - 10.1371/journal.pntd.0004132
M3 - Article
C2 - 26506128
AN - SCOPUS:84959229975
VL - 9
JO - PLoS Neglected Tropical Diseases
JF - PLoS Neglected Tropical Diseases
SN - 1935-2727
IS - 10
M1 - e0004132
ER -