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

• প্রধান লেখক: Alexander B Taylor (Author), Livia Pica-Mattoccia (Author), Chiara M Polcaro (Author), Enrica Donati (Author), Xiaohang Cao (Author), Annalisa Basso (Author), Alessandra Guidi (Author), Anastasia R Rugel (Author), Stephen P Holloway (Author), Timothy J C Anderson (Author), P John Hart (Author), Donato Cioli (Author), Philip T LoVerde (Author)
• বিন্যাস: গ্রন্থ
• প্রকাশিত: Public Library of Science (PLoS), 2015-01-01T00:00:00Z.
• বিষয়গুলি: article
• অনলাইন ব্যবহার করুন: Connect to this object online.

সংক্ষিপ্ত

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. These findings have important implications for the design, syntheses, and dosing of new OXA-based antischistosomal compounds.

উপাদানের বিবরণ

1935-2727
1935-2735
10.1371/journal.pntd.0004132