Drug Search For Leishmaniasis

¿What is Leishmaniasis?

Leishmaniasis is a disease caused by a parasite called Leishmania and is transmitted to humans through the bite of an insect vector (Photo 1). There are over 2 million people affected in 98 countries all over the world, where the disease occurs. In addition, a smaller number of cases occur in non-endemic countries, as a result of ecotourism practices by inhabitants of the non-endemic areas to endemic countries.

Photo 1.

The disease occurs basically in three clinical forms, cutaneous, mucocutaneous and visceral, and may depend on the Leishmania species. The cutaneous form (LC) is an infection that causes ulcers on uncovered areas of skin, mainly face, arms, legs, back (Photo 2), where the insect vector bites. The mucocutaneous leishmaniasis (MCL) is characterized by lesions in the mucous membranes of the mouth, throat, nose, (and surrounding tissue), (Photo 3).Tissue and cartilage of these membranes can be destroyed by erosion and ulceration. These two forms of the disease usually leave disfiguring scars or injuries that stigmatize and affect the quality of life of patients by altering the perception that people have of themselves and each patient's perception of himself. These lesions are generally difficult to resolve. Visceral leishmaniasis (VL) is the most severe of the three types and is characterized by invasion of the parasites to bone marrow, liver, spleen and lymphatic nodes. The symptoms include fever, weight loss, enlarged of liver, spleen and lymph nodes as a result of infection, in addition to anemia and bleeding problems etc. The disease can be fatal if not treatment is timely and adequately administered.

Photo 2.

Photo 3.

Availability of medicines, problems with these and new therapeutic options.

So far, pentavalent antimony-based compounds together with amphotericin B, pentamidine isethionate and miltefosine, are the most commonly drugs available for the treatment of all forms of leishmaniasis. However, the use of these drugs have numerous disadvantages, some more than others, but the reality is that none has proved ideal. Disadvantages exhibited by these four treatment options include the following:

- High doses administered to the patient are associated with moderate to high toxicity, which sometimes has caused deaths.

- The need for prolonged treatment regimens that favor non-adherence or treatment discontinuation of the patients, which in turn favors the emergence of resistant strains or decreased sensitivity to the drug.

- The cost is expensive for most countries where leishmaniasis is endemic.

- The little or no motivation that has the pharmaceutical industry to invest in research and development of drugs for leishmaniasis has led to this disease as one of those included in the group of orphaned or neglected diseases.

Because of this, the World Health Organization (www.who.int/en-Link this web site) through its Special for Research in Tropical Diseases and known as Tropical Diseases Research (TDR-link) program and Diseases orphans or Neglected as the Neglected Tropical Diseases (NTD-link), in collaboration with various Non-Governmental Organizations (NGOs) and the Drugs for neglected Disease Initiative (DNDi-link) have declared a research priority in the discovery and development of new treatments that are accessible, safe, efficient, short, manageable and affordable to improve the quality of life of patients. This emphasizes the importance of finding new drugs that are safe and effective in managing the disease.

Opportunities of sequenced genomes, databases and open access computational tools available facilitate the search for new anti-Leishmania drugs.

The availability of sequenced and annotated genomes, specialized databases with relevant information, along with many computational tools available online and open access, is now possible to develop initiatives to look for drugs or vaccines in a more rational way. However, the need for computational cluster with good processability and storage, limits these initiatives in less developed, and even in some developed countries. The availability of initiatives such as the World Community Grid, IBM, makes it easier to carry out projects in this and other topics requiring high computing power.

What we do in the PECET in collaboration with IBM World Community Grid to address the problem of limited number of drugs to treat leishmaniasis.

Given the drawbacks that arise with existing drugs to treat leishmaniasis, what we intend to make is searching through many medications that are currently used to treat other diseases, which may have also anti-Leishmania activity. For this we will face 53 Leishmania protein structures with solved three-dimensional structures and deposited in the PDB database and 530 modelled structures (583 in total) against approximately 600,000 compounds obtained and filtered from the Zinc database. This will be done using a computational tool known as docking, which seeks the drug that binds with better affinity to the molecular structure of each of the 53 proteins of Leishmania and the 530 modelled. Drugs that better interact with any of these proteins are commercially acquired to evaluate its effect in vitro using automated systems with GFP transfected parasites and in vivo models. These methods have previously been standardized and are under use in PECET, University of Antioquia.

Leishmaniasis, a preventable and curable disease.

Despite the considerable number of cases occurring annually worldwide, and that this number has a tendency to increase, the disease is potentially preventable and curable and the number of cases per year could be reduced considerably and in some particular foci you might even eradicate.

How to prevent it:

Since there is no vaccine against leishmaniasis; education and treatment administration in affected communities is essential. The education campaign should be focused on properly educate this populations in themes such as:
- Who causes the disease?.
- How and who transmits the diseases?.
- Where are potential breeding sites of the insect vector?.
- What time of day are more likely to be in contact with the insect vectors?.
- What measures can be used to avoid contact with the insect vectors?.
- How the disease is treated?.
- What not to do when you think the disease was acquired?.

How to cure:

First thing to cure the disease properly, is to know whether the lesion (for cutaneous leishmaniasis or mucocutaneous) or the symptoms presented by the patient (for visceral leishmaniasis) is caused by the parasite, Leishmania. The reason is because the lesion, in the case of cutaneous or mucocutaneos leishmaniasis, or the symptoms, for visceral leishmaniasis may resemble diseases other than leishmaniasis. The treatment of first choice is generally based on pentavalent antimony, however in some countries first choice of drugs of may vary, especially those with high rates of resistance to antimonials by these parasites. In addition, provide a timely and appropriate treatment is vital, because the man's role as a reservoir of the disease, increasingly takes more strength. Thus, implement timely treatment would prevent that the insect vectors become infected after biting infected people looking for a new blood ingestion. The correct combination of these two strategies is essential to try to reduce the number of people infected with Leishmania.