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Research: Drug Search for Leishmaniasis: Project Details
 
About the Project

Leishmaniasis is a tropical disease caused by a parasite transmitted by specific insects. Infections of this disease have been increasing - with over two million people affected last year. Existing treatments can have severe side effects, including death. Currently, pharmaceutical companies have not been investing in extensive research to combat this disease. Therefore, the researchers at the University of Antioquia in Medellín, Colombia, are running a project on World Community Grid to search for chemical compounds which may lead to new drugs for treating this disease.


Leishmaniasis is caused by a single celled protozoan parasite. The genus of this protozoan is Leishmania. It is transmitted between human and animal hosts via the female sand fly. In the Americas, the genus of the sand fly is Lutzomyia and elsewhere it is Phlebotomus. The insect injects humans or other animals with promastigotes, the infective stage of the parasite. Once injected into the skin, the promastigote infects immune system cells such as macrophages and other mononuclear phagocytic cells. Within these cells, the promastigote transforms into the tissue stage of the parasite, known as amastigote, which multiplies inside the cell by simple division, moving on to infect other phagocytic mononuclear cells. Various factors of the parasite and host determine which form of the diseases appears in the host. The insects become infected by sucking infected cells of the host during a blood meal. In the insect´s gut, the cells rupture releasing amastigotes, which are transformed back into promastigotes. They multiply and develop in the insect's gut. After several days, depending on the species, the parasites migrate to the mouthparts of the insect, where they are ready again to be transmitted to a host, during the next blood meal.


The disease has three clinical forms:

  • cutaneous - affecting the surface skin consisting mostly of ulcerated lesions, warty lesions or spots.
  • mucocutaneous - affecting mucous membranes, particularly from the nose, laryngeal and pharynx.
  • visceral - affecting bone marrow or internal organs, such as the liver, spleen and lymph nodes. Symptoms can include anemia, clotting problems, weight loss, enlarging of the spleen, liver and lymph nodes.

The classical treatments for all forms of Leishmaniasis are certain compounds of pentavalent antimony (e.g. sodium stibogluconate and meglumine antimoniate). These compounds can have severe side effects, including death. Furthermore, drug resistant parasites are causing major problems in many endemic countries. Several additional drugs such as Pentamidine and Amphotericin B have been used with variable success, but these drugs also have serious side effects and are expensive and difficult to administer, limiting their use as drugs of choice. More recently, Miltefosine (an oral drug) has been used with variable success in Central and South America against cutaneous Leishmaniasis and for visceral Leishmaniasis in India. A phase IV trial of this drug in India has shown an increase in the relapse rate, indicating that drug resistance may develop quickly. The visceral form mainly affects children, who can die if adequate treatment is not provided promptly.


The complete genomes of several Leishmania species have been decoded and are providing information about proteins and processes essential for the survival of the parasite. Certain Leishmania proteins have been identified as targets using information about the genomes and through prior laboratory experiments and computational work. If drugs can be developed to disable these proteins, they may prove to be an effective treatment for the disease. The first step in drug development is to find chemical compounds which attach to the target protein in a manner that disables the protein's function, thus preventing the progression of the disease. To accelerate the search for potential drugs against Leishmaniasis, the computing power of World Community Grid will be used to screen millions of potential chemical compounds as possible drug treatment candidates. Instead of performing expensive and time-consuming laboratory experiments, simulations of these millions of experiments will be performed using the software running on World Community Grid's member computers.


A software program called VINA from The Scripps Research Institute in La Jolla, California, will be used to perform the virtual chemistry experiments, more precisely known as molecular dockings. Molecular docking is the process of determining how well two chemical compounds (molecules) bind together. One of the molecules is designated as the target, in this case one of several proteins, essential for the parasite's survival. The other compound is from a collection of millions of compounds from various drug data bases, cataloging known compounds and their exact atomic structure. The docking experiments position the two compounds in all possible orientations and then compute the binding energy, which tells how well they stick together. If a compound binds to the target protein, it may be useful in disabling the function of that protein and thus reducing parasite multiplication and the progress of the disease.


The VINA calculations will be used to identify the most promising chemical compounds that may inhibit these proteins. The computer computations involved are very intensive and would take about 120 years to test the 12 million compounds against 70 Leishmania proteins, if using machines normally available to the researchers. World Community Grid will be able to reduce the time required to less than one year. Information about the best candidate compounds will be published by the scientists, and this information will be available in the public domain for other scientists to build upon with their research. Further laboratory work using the best candidates identified by the VINA computations could lead to the development of better drugs to fight Leishmaniasis.



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