Molecular Basis of Antimony Treatment in Leishmaniasis

Abstract

Leishmaniasis is a disease that affects 2 million people and kills 70000 persons every year. It is caused by Leishmania species, which are human protozoan parasites of the trypanosomatidae family. Trypanosomatidae differ from the other eukaryotes in their specific redox metabolism because the glutathione/glutathione reductase system is replaced by the unique trypanothione/trypanothione reductase system. The current treatment of leishmaniasis relies mainly on antimonial drugs. The crystal structures of oxidized trypanothione reductase (TR) from Leishmania infantum and of the complex of reduced TR with NADPH and Sb(III), reported in this paper, disclose for the first time the molecular mechanism of action of antimonial drugs against the parasite. Sb(III), which is coordinated by the two redox-active catalytic cysteine residues (Cys52 and Cys57), one threonine residue (Thr335), and His461' of the 2-fold symmetry related subunit in the dimer, strongly inhibits TR activity. Because TR is essential for the parasite survival and virulence and it is absent in mammalian cells, these findings provide insights toward the design of new more affordable and less toxic drugs against Leishmaniasis.

TTAS a new stilbene derivative that induces apoptosis in Leishmania infantum

“…Leishmaniasis treatment is based on parenteral administration of highly toxic drugs including pentavalent antimonials, amphotericin B in its liposomal formulation (Ambisone) and pentamidine (Murray et al, 2005;Croft et al, 2006;Baiocco et al, 2009;Palumbo, 2009). Recently, oral administration of miltefosine has emerged as an alternative approach (Herwaldt, 1999).…”

“…To date, the greatest prevalence of Leishmania-HIV co-infection has been in the Mediterranean basin (Cruz et al, 2006;Colomba et al, 2009). Current leishmaniasis treatment is based on chemotherapy, which relies on a handful of drugs with serious limitations such as high cost and toxicity, difficult route of administration, and lack of efficacy in endemic areas (Murray et al, 2005;Croft et al, 2006;Baiocco et al, 2009;Palumbo, 2009). Extensive evidence from studies in animal models indicates that good protection can be achieved by immunization, however, to date no vaccine is available and also for this reason there is an urgent need to develop safer, cheaper and more effective antileishmanial agents.…”

Antiparasitic activities of novel ruthenium/lapachol complexes

“…It is estimated that leishmania disease causes about seventy thousand deaths annually and malaria kills around 1 million children only in Africa [1]. The first line treatment for leishmaniasis still relies on the use of pentavalent antimonials, although other drugs are also used for the treatment of Leishmania infection, such as pentamidine isethionate, amphotericin B and miltefosine [2,3].…”

Inhibitory Effect of Silver Nanoparticles on Trypanothione Reductase Activity and Leishmania infantum Proliferation

“…These experiments show that TR is strongly inhibited in vitro by silver in both oxidized and reduced form. In fact, the inhibition constant measured for Sb(III) is 1.5 μM, 8 whereas the inhibition constants calculated for Ag(0) The ability of silver to inhibit TR is explained at the molecular level by the crystal structure of reduced L. infantum TR in complex with NADPH and silver solved at 3.3 Å resolution (see Supporting Information) (Figure 1). Indeed, the difference electron density map F o -F c shows the presence of a strong peak in both monomers, corresponding to the Sb(III) binding site, that has been assigned to a silver atom with an occupancy of 80% in both subunits (Figure 2).…”