Effects of Phospholipid Analogues on Trypanosomatids
Wanderley de Souza, Joseane Godinho, Emile Barrias, Marina Roussaki, Juliany C. F. Fernandes Rodrigues and Theodora Calogeropoulou.
from: Molecular Biology of Kinetoplastid Parasites (Edited by: Hemanta K. Majumder). Caister Academic Press, U.K. (2018) Pages: 221-242.
Diseases caused by pathogenic protozoa that belong to the Trypanosomatidae these include Chagas' disease and sleeping sickness, which are caused by Trypanosoma cruzi and Trypanosoma brucei (rhodesiense and gambiense subspecies), respectively, and the various forms of leishmaniasis, caused by several species of the Leishmania genus. Although significant efforts have been directed at developing new chemotherapeutic strategies against trypanosomatids, the compounds routinely used in clinical practice are those that were identified many years ago (pentavalent antimonials, pentamidine, or liposomal amphotericin B for leishmaniasis; nifurtimox or benzinidazole for Chagas disese;). Several groups are working on the identification of new and more specific drug targets in trypanosomatids. One important recognized target is the phospholipids (PLs) biosynthesis in view of the important role played by these molecules in cell structure and functions. In this chapter we review basic aspects of the PLs biosynthetic pathways both in mammalian cells and in trypanosomatids. In addition special emphasis is given to the Phospholipid Analogues (PA) that constitute a new class of pharmaceutical compounds that exhibit excellent biocompatibility and an especial amphiphilicity making them appropriate to be employed as drugs with broad biological activity. The various possibilities to synthesize these compounds either by organic and/or enzymatic synthetic steps are discussed. Mention is made to the process of molecular hybridization which allows the synthesis of new hybrid molecules by combining two pharmacophores such as PAs with Trifluralin. Several PAs have been tested against parasitic protozoa and some of them have shown excellent anti parasite activity. One of them, miltefosine, has been introduced in clinics to treat leishmaniasis. We also review the effect of several PAs on the growth, morphology, cell cycle, lipid accumulation, and mitochondrion function in the parasites. These compounds are able to kill the parasites through mechanisms such as autophagy and/or a apoptotic-like cell death process read more ...