Sterol Biosynthesis Pathway as an Alternative for the Anti-Protozoan Parasite Chemotherapy

Abstract

Sterols play an essential role in the physiology of eukaryotic cells; they play a pivotal role in the normal structure and function of cell membranes and also act as precursors for the synthesis of several different molecules like steroid hormones. Trypanosomatids and fungi have an essential requirement of ergosterol and other 24-alkyl sterols, which are absent in mammalian cells, for their survival and growth. At least 20 metabolic steps are necessary to synthesize sterols as cholesterol and ergosterol with the involvement of different specific enzymes. Some enzymes have been studied in detail in order to find new inhibitors that are able to abolish the parasite growth in vitro; besides, they also promote the curative efficacy in murine models of infection, thus opening new possibilities to introduce new drugs for the treatment of leishmaniasis and Chagas' disease. Sterols biosynthesis inhibitors (SBIs) can potentially be used as a chemotherapeutic agent against trypanosomatids. Actually, there are several drugs that interfere with the SB pathway, and some of them are already in clinical trials, such as posaconazole, and a new pro-drug, the ravuconazole. Furthermore, new approaches are being used, such as the combination of drugs, to reduce the resistance and minimize toxic effects. In this review, we discuss the main steps of the SB pathway, showing each enzyme involved in the steps, as well as the antiproliferative, physiological, biochemical, and ultrastructural effects of the several known inhibitors.