Reduction of pentavalent antimony(SbV) by trypanothione and formation of a binary and ternary complex of antimony(III) and trypanothione

Abstract

Leishmaniasis is affecting more than 10 million people worldwide. Several antimony compounds have been used for the treatment of leishmaniasis for decades. However the mechanisms of action of the antimony drugs still remain unknown. One of the targets of the antimony drugs is thought to be trypanothione, which is a major low molecular mass thiol inside the parasite,[[1]] and the anti-leishmanial activity of SbV is dependent on its reduction to trivalent (SbIII) inside parasites.[[2]] Surprisingly, pentavalent antimony (SbV) can be rapidly reduced to its trivalent state by trypanothione at mildly acidic conditions at 310 K (k=4.42 M-1 min-1, pH 6.4), in contrast to it’s analogy, the glutathione (k< 1.9x 10-2 M-1 min-1, pH 6.4).[[3]] The reduced SbIII subsequently binds to trypanothione to form an SbIII-trypanothione complex. The binding is pH dependent and is the strongest at biological pH with the stability constant log K=23.6 at 298 K (0.1 M NaNO3). Addition of low molecular monothiol ligands such as glutathione and cysteine to the SbIII-trypanothione complex leads to the formation of a ternary complex. Thiolates from both trypanothione and monothiol bind to SbIII center. In spite of being thermodynamically stable, the complex is kinetically labile and the free and bound forms of thiolates exchange on the 1H NMR time-scale. The formation of the ternary complex is important as it may play a role in the transport of antimony and the antileishmaniasis properties of the drugs are probably via the formation of a complex between of SbIII-trypanothione and enzymes.

This work was supported by the Research Grant Council of Hong Kong, University of Hong Kong (UGC) and Hung Hing Ying Physical Sciences Research Fund. We are grateful to the University of Hong Kong for a Research Studentship (for S. Yan).