Structural Differences in Translation Initiation between Pathogenic Trypanosomatids and Their Mammalian Hosts.

Canonical mRNA translation in eukaryotes begins with the formation of the 43S pre-initiation complex (PIC). Its assembly requires binding of initiator Met-tRNAiMet and several eukaryotic initiation factors (eIFs) to the small ribosomal subunit (40S). Compared to their mammalian hosts, trypanosomatids present significant structural differences in their 40S, suggesting substantial variability in translation initiation. Here, we determine the structure of the 43S PIC from Trypanosoma cruzi, the parasite causing Chagas disease. Our structure shows numerous specific features, such as the variant eIF3 structure and its unique interactions with the large rRNA expansion segments (ESs) 9S, 7S, and 6S, and the association of a kinetoplastid-specific DDX60-like helicase. It also reveals the 40S-binding site of the eIF5 C-terminal domain and structures of key terminal tails of several conserved eIFs underlying their activities within the PIC. Our results are corroborated by glutathione S-transferase (GST) pull-down assays in both human and T. cruzi and mass spectrometry data.

Nanotechnological Strategies for Treatment of Leishmaniasis--A Review.

The World Health Organization (WHO) estimates that more than one billion people suffer from neglected tropical diseases. Leishmaniasis is a widespread disease, affecting 12 million people around the world with about 1­2 million estimated new cases occurring every year. Although pentavalent antimonial drugs are the most frequently prescribed treatments for leishmaniasis, they produce severe side effects, including cardiotoxicity and hepatotoxicity. Other compounds, such as amphotericin B, pentamidine and miltefosine, are second choice drugs, but they also produce side effects that can endanger the patient's life. Nowadays, there are two approaches to develop new therapies: one is the search for new drugs and the other is the optimization of actual drug formulation. Traditional drug discovery takes 10 to 12 years in general and involves high costs; around one billion dollars on average to develop a drug. A possibility to improve leishmaniasis treatment would be the application of nanotechnology-drug delivery systems which can enhance the therapeutic potency of existing drugs by optimizing their adsorption, distribution, metabolism and excretion (ADME) and reducing toxicity. In this review we will discuss examples how nanotechnology-drug delivery systems have been used to improve the therapeutic aspects of existing antileishmanial drugs.