Structural and functional characterization of the enantiomers of the antischistosomal drug oxamniquine
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. In conclusion, these findings have important implications for the design, syntheses, and dosing of new OXA-based antischistosomal compounds.
- Authors:
-
- Univ. of Texas Health Science Center, San Antonio, TX (United States)
- Institute of Cell Biology and Neurobiology, CNR, Rome (Italy)
- Institute of Chemical Methodologies, CNR, Rome (Italy)
- Texas Biomedical Research Institute, San Antonio, TX (United States)
- Univ. of Texas Health Science Center, San Antonio, TX (United States); South Texas Veterans Health Care System, San Antonio, TX (United States)
- (
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC)
- OSTI Identifier:
- 1240269
- Grant/Contract Number:
- AC02-06CH11357
- Resource Type:
- Accepted Manuscript
- Journal Name:
- PLoS Neglected Tropical Diseases (Online)
- Additional Journal Information:
- Journal Name: PLoS Neglected Tropical Diseases (Online); Journal Volume: 9; Journal Issue: 10; Journal ID: ISSN 1935-2735
- Publisher:
- Public Library of Science
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; enantiomers; crystal structure; schistosoma mansoni; high performance liquid chromatography; schistosoma; hydrogen bonding; enzyme structure; protein structure
Citation Formats
Taylor, Alexander B., Pica-Mattoccia, Livia, Polcaro, Chiara M., Donati, Enrica, Cao, Xiaohang, Basso, Annalisa, Guidi, Alessandra, Rugel, Anastasia R., Holloway, Stephen P., Anderson, Timothy J.C., Hart, P. John, Cioli, Donato, LoVerde, Philip T., VA), Texas-HSC), UTSMC), and CNR-Genoa). Structural and functional characterization of the enantiomers of the antischistosomal drug oxamniquine. United States: N. p., 2015.
Web. doi:10.1371/journal.pntd.0004132.
Taylor, Alexander B., Pica-Mattoccia, Livia, Polcaro, Chiara M., Donati, Enrica, Cao, Xiaohang, Basso, Annalisa, Guidi, Alessandra, Rugel, Anastasia R., Holloway, Stephen P., Anderson, Timothy J.C., Hart, P. John, Cioli, Donato, LoVerde, Philip T., VA), Texas-HSC), UTSMC), & CNR-Genoa). Structural and functional characterization of the enantiomers of the antischistosomal drug oxamniquine. United States. https://doi.org/10.1371/journal.pntd.0004132
Taylor, Alexander B., Pica-Mattoccia, Livia, Polcaro, Chiara M., Donati, Enrica, Cao, Xiaohang, Basso, Annalisa, Guidi, Alessandra, Rugel, Anastasia R., Holloway, Stephen P., Anderson, Timothy J.C., Hart, P. John, Cioli, Donato, LoVerde, Philip T., VA), Texas-HSC), UTSMC), and CNR-Genoa). Tue .
"Structural and functional characterization of the enantiomers of the antischistosomal drug oxamniquine". United States. https://doi.org/10.1371/journal.pntd.0004132. https://www.osti.gov/servlets/purl/1240269.
@article{osti_1240269,
title = {Structural and functional characterization of the enantiomers of the antischistosomal drug oxamniquine},
author = {Taylor, Alexander B. and Pica-Mattoccia, Livia and Polcaro, Chiara M. and Donati, Enrica and Cao, Xiaohang and Basso, Annalisa and Guidi, Alessandra and Rugel, Anastasia R. and Holloway, Stephen P. and Anderson, Timothy J.C. and Hart, P. John and Cioli, Donato and LoVerde, Philip T. and VA) and Texas-HSC) and UTSMC) and CNR-Genoa)},
abstractNote = {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. In conclusion, these findings have important implications for the design, syntheses, and dosing of new OXA-based antischistosomal compounds.},
doi = {10.1371/journal.pntd.0004132},
journal = {PLoS Neglected Tropical Diseases (Online)},
number = 10,
volume = 9,
place = {United States},
year = {Tue Oct 20 00:00:00 EDT 2015},
month = {Tue Oct 20 00:00:00 EDT 2015}
}
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