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Leishmaniasis

The disease

Leishmaniasis is a disease caused by a parasitic protozoan of the genus Leishmania, with more than 20 different species. It is transmitted to humans by the bite of an infected female sandfly. The disease can present three clinical manifestations: visceral (the most severe, known as kala-azar, which can be fatal), cutaneous (the most common) and mucocutaneous. research ISTUN's design lines of research focus on new compounds, the development of more effective pharmaceutical formulation strategies as well as the search for new therapeutic targets and the improvement of diagnostic techniques.

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Prevalence

It is estimated that 1.3 million new cases occur each year, and 20-30 thousand deaths are reported by WHO (WHO, 2013). However, these figures are probably underestimated, as many cases go undiagnosed and the number of infected but asymptomatic people is higher than the number of overt cases. It is associated with environmental changes, malnutrition, population displacement, poor housing conditions and weakened immune systems. It affects the world's poorest populations and is present in the Mediterranean basin (including Spain), South-East Asia, East Africa and Latin America. Importantly, Spain is the country in the Mediterranean basin with the highest number of reported cases of Leishmania/HIV/AIDS co-infection, with patients presenting a clinical picture indistinguishable from that seen in patients infected only with Leishmania.

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Treatment and diagnosis

Treatment of leishmaniasis depends on several factors: the form of the disease, the species of Leishmania that causes it and the geographical location where it occurs. A number of drugs are currently available that are relatively effective but not without drawbacks such as the development of resistance, difficulty of administration and high toxicity. It is now a priority to identify therapeutic targets, design and develop new drugs that can be administered orally or topically, are less toxic and less expensive.

Diagnosis includes, among others, invasive tests, together with the study of the clinical manifestations of the disease development . However, in the case of cutaneous leishmaniasis, these manifestations are non-specific and can be confused with other diseases with cutaneous involvement. Moreover, especially in the visceral form, many infected patients are asymptomatic, hence the importance of early diagnosis to detect the presence of parasites in these individuals.

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Nested applications

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New formulations

Our line of research explores the potential of using pharmaceutical formulation strategies (nanoparticles) to solve some of the problems of current leishmaniasis treatments. Nanoparticles may enable drugs to be effective at lower and less toxic doses by selectively targeting their site of action, as they are naturally captured by macrophages that also harbour the parasites. In addition, they may also allow treatments to be administered orally or topically by facilitating the passage of drugs across biological barriers.

Specifically, we studied:

The relationship between the physico-chemical properties of the nanoparticles (material and surface charge) and their ability to activate macrophages and thereby eliminate parasites. This combines the chemotherapy of the drug they carry with their immunostimulant capacity. It also allows nanoparticles to be used as adjuvants for vaccination, another major pending task in the fight against leishmaniasis.
The usefulness of nanoparticles in overcoming resistance to conventional treatments such as antimonial derivatives by improving their intracellular penetration.
Topical formulations for the local treatment of cutaneous leishmaniasis by photodynamic therapy.
Bioadhesive nanoparticles to enable oral absorption of drugs with leave bioavailability by this route of administration

Compound Synthesis

Our group of work on pharmacotherapy in leishmaniasis proposes to tackle this pathology through the design, the synthesis and identification of new families of drugs with this activity, as well as their optimisation based on the study of the relationship between biological structure and activity Chemistry.

Specifically, we focus on the synthesis of new symmetric and asymmetric molecules with a structure containing S and/or Se, in various oxidation states, as well as leishmania fragments, whose lethal efficacy has been demonstrated, by applying the "Medicinal Chemical Hybridisation" strategy. Structural modulation will be designed to optimise potency, improve university entrance exam and ADME properties. In relation to the possible mechanism of action, inhibition of Trypanothione Reductase and other enzymes involved in parasitic redox processes is proposed.

Therapeutic Targets and Molecular Diagnostics

Molecular diagnostics. The knowledge of the genome of several Leishmania species makes it easier to tackle diagnostic problems. Our research project group focuses on the search, study and characterisation of genes that can be used as diagnostic markers for the early detection of the disease.

Therapeutic targets. Our research team analyses Leishmania genes involved in cell proliferation and differentiation and infectivity. We study its expression throughout the parasite's life cycle and in infective forms. The implication of this gene in the mechanisms of cell differentiation relates it to the acquisition of infectivity by the parasite. Interpreting this mechanism is essential to understand the transmission and progression of the disease and would allow us to characterise new therapeutic targets in the fight against these diseases.