Discovery and study of yinp as a new therapeutic target for leishmaniasis

Resumen

Neglected tropical diseases (NTDs) – an assorted group of diseases that prevail in tropical and subtropical regions (~149 countries) – affect more than one billion people and cost billions of dollars every year mostly in developing areas. Parasitic and bacterial NTDs include three soil-transmitted helminth infections (ascariasis, hookworm infection and trichuriasis), lymphatic filariasis, onchocerciasis, dracunculiasis, schistosomiasis, Chagas’ disease, human African trypanosomiasis, leishmaniasis, Buruli ulcer, leprosy and trachoma. Populations living in poverty, without adequate sanitation and in close contact with infectious vectors and domestic animals and livestock are those worst affected. NTDs are among ones of the most common pathologies affecting several hundred million people living on less than $2 per day. In addition, these diseases cause approximately 534,000 deaths annually. Therefore, through the newly established Global Network for Neglected Tropical Diseases, with updated guidelines for drug administration issued by the World Health Organization (WHO), partnerships are coordinating their activities in order to launch a more integrated assault against this group of diseases. The World Health Assembly’s ambitious goal was to eradicate or control the seven most prevalent neglected diseases by 2020, African trypanosomiasis, leishmaniasis and Chagas disease among them. Although strategies to control and eliminate these three diseases are available, ultimately, success will almost certainly depend on access to new and cost-effective products to improve control. In response to this issue, partnerships had been established to address product development against NTDs. These partnerships for product development are either exploiting newly completed genome projects for pathogens in order to identify potential drug targets using high-throughput screenings or taking traditional approaches to drug development and clinical testing. The economic impact derived from the achievement of those ambitious commitments from the World Health Assembly on NTDs would be an important model in disease control and poverty reduction. Currently, the wide range of pathogen genomes that have been sequenced and are openly accessibly to date can be exploited for comparative genomic and transcriptomic analyses and enable researchers to identify parasite-specific targets. Despite of the evolutionary distance between protozoan and their mammalian hosts, both groups have diverging proteomes but also highly conserved domains within several proteins. If these proteins are essential for relevant stages of the pathogenicity or are involved in critical cellular processes, they should constitute ideal targets for therapeutic benefits. One of these proteins are the ribosomal proteins. In fact, many drugs used in clinic target the ribosome by interfering with the protein synthesis machinery. Furthermore, targeting human ribosome may induce protein synthesis deregulations, and in extremely proliferating cancer cells, this strategy represents a novel approach for anti-cancer therapy. For example, the overexpression of the ribosomal protein Pescadillo (Pes) has been described in several cancers (liver, ovarian, colorectal, breast…). On the other hand, it is well known that some drugs, such as miltefosine, initially designed as anti-tumoral agents are currently used against NTDs. Based on data related to human Pes, we were prompted to explore this target in trypanosomatids. Accordingly, to open new avenues for the development of next generation of antiprotozoan drugs, the aim of our Ph.D project was the comprehensive study of a newly discovered trypanosomatid protein (YinP from Leishmania major) as a novel therapeutic target for Leishmaniasis.