Ergosterol biosynthesis and drug development for Chagas disease

Abstract

This article presents an overview of the currently available drugs nifurtimox (NFX)

Short-term therapy with simvastatin reduces inflammatory mediators and heart inflammation during the acute phase of experimental Chagas disease

“…Inhibition of the growth of epimastigotes of T. cruzi has been observed upon treatment with 10-0 mg/mL of statin (lovastatin) that may be a result of the inhibition of C14 acetate incorporation into parasite sterols (Florin-Christensen et al 1990). T. cruzi, similar to many fungi and yeasts, requires specific sterols for its survival during different stages of its life cycle (Urbina 2009). In our in vitro investigation, the growth of cultured epimastigotes was reduced by the presence of simvastatin in a dose-dependent fashion (1.9 mM-2.5 mM).…”

Trypanosoma cruzi benznidazole susceptibility in vitro does not predict the therapeutic outcome of human Chagas disease

“…Although the intracellular amastigote model is considered the most consistent indicator of in vivo activity, a number of tests showed a strong correlation between the activity of compounds against epimastigote cultures and their activity in mice (Croft 1986, Urbina 2009). Nevertheless, differences of several orders of magnitude of the IC 50 values of epimastigotes and amastigotes were reported.…”

“…Ergosterol biosynthesis inhibitors are currently the most advanced candidates for new anti-T. cruzi agents, as they have been shown to have curative activity in chronic infections in mice and to be active against NF and BZ-resistant T. cruzi strains (Urbina 2009). Ergosterol biosynthesis inhibitors are poised for clinical trials in Chagas disease patients in the short term.…”

Chagas disease: Present status of pathogenic mechanisms and chemotherapy

“…Numerous natural and synthetic chemical compounds with potential trypanocidal activity are being added to the list, including allopurinol and its analogues, ketoconazole and itraconazole (antifungal imidazoles), quinones, diverse nitroheterocyclic derivatives, antioxidants and other drugs in clinical use, such as phenothiazines (Apt et al, 2005;Maya et al, 2007;Urbina, 2009b). Some compounds, including sterol biosynthesis, cysteine protease and pyrophosphate metabolism inhibitors, have completed pre-clinical studies and are poised for clinical trials in Chagas disease patients (Reithinger et al, 2009;Urbina, 2009a). Yet, most of the studied compounds, for diverse reasons, such as insensibility or resistance, solubility, toxicity or low clinical efficacy, have not proven to be better than Nx or Bz.…”