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


RESULTS
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
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.
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.
Alexander B
AB
Taylor
Institute of Cell Biology and Neurobiology, CNR, Rome, Italy.
Livia
L
Pica-Mattoccia
Institute of Chemical Methodologies, CNR, Rome, Italy.
Chiara M
CM
Polcaro
Institute of Chemical Methodologies, CNR, Rome, Italy.
Enrica
E
Donati
Departments of Biochemistry, the University of Texas Health Science Center, San Antonio, Texas, United States of America.
Xiaohang
X
Cao
Institute of Cell Biology and Neurobiology, CNR, Rome, Italy.
Annalisa
A
Basso
Institute of Cell Biology and Neurobiology, CNR, Rome, Italy.
Alessandra
A
Guidi
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.
Anastasia R
AR
Rugel
Departments of Biochemistry, the University of Texas Health Science Center, San Antonio, Texas, United States of America.
Stephen P
SP
Holloway
Texas Biomedical Research Institute, San Antonio, Texas, United States of America.
Timothy J C
TJ
Anderson
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.
P John
PJ
Hart
Institute of Cell Biology and Neurobiology, CNR, Rome, Italy.
Donato
D
Cioli
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.
Philip T
PT
LoVerde
D000818:Animals; D000871:Anthelmintics / Q000737:chemistry* / Q000494:pharmacology*; D002845:Chromatography; D018360:Crystallography, X-Ray; D005260:Female; D051379:Mice; D008958:Models, Molecular; D010073:Oxamniquine / Q000737:chemistry* / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests; D011485:Protein Binding; D011487:Protein Conformation; D012550:Schistosoma mansoni / Q000187:drug effects / Q000201:enzymology; D013237:Stereoisomerism; D015238:Sulfotransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry*
D000871:Anthelmintics; D010073:Oxamniquine; D015238:Sulfotransferases