COST Action B22 on
"Drug development for parasitic diseases"
2003-2007
Background
Parasitic diseases are a major threat to the health of the human
population throughout the world. Despite this fact, there is a
limited number of effective drugs available for the treatment or
prophylaxis of many parasitic diseases, in particular the
protozoal diseases malaria, leishmaniasis, human African
trypanosomiasis (sleeping sickness) and South American
trypanosomiasis (Chagas disease). Although malaria, leishmaniasis
and trypanosomiasis are major causes of morbidity and mortality in
both tropical and subtropical regions of the world, treatment is
inadequate due to limited drugs and widespread resistance. The
chemotherapy of malaria, a disease that causes 250 million
infections and up to 2 million deaths per annum, has been
undermined by the development of resistance by the Plasmodium
parasite to the standard drugs chloroquine and
pyrimethamine-sulphadoxine. The first line drugs for used for the
treatment of leishmaniasis and the trypanosomiases, antimonials,
arsenicals and nitroheterocyclic compounds, have poor efficacy,
toxic side effects and require long courses of treatment. Drug
treatment for immuno-compromised patients with opportunistic
parasites, for example cryptosporidiosis, microsporidiosis and
toxoplasmosis, is also limited. In addition some protozoan
parasites of animals have a major impact on human health and
economic development either as a reservoir for human infection,
for example leishmaniasis and cryptosporidiosis, or as a major
threat to live stock productivity, for example trypanosomiasis in
Africa and Asia.
There are three major tasks facing the search for new anti-parasitic drugs. Firstly, the identification of novel drug targets, previously based upon biochemical and cellular studies that characterise metabolic pathways and cell structures that are different between parasite and host, has been revolutionised by the advent of the genomics. Already the genome sequences of pathogenic bacteria and fungi has enabled the characterisation of novel metabolic pathways in Mycobacterium tuberculosis and role of each gene in the model yeast, Saccharomyces cerevisiae. Within the next three years, the genome sequences of the parasites that cause malaria, leishmaniasis and trypanosomiasis will be completed and the expansion of molecular and biochemical data will have a major impact on drug research. The problem will be to identify differences that are potential drug targets, for example, parasite-specific genes essential for infection and pathogenesis, novel metabolic pathways, the unique parasite-specific mechanisms of gene regulation and RNA processing. Techniques to analyse the protein profile of the parasite to identify functionally important genes (proteomics) and improved technologies for transfection, complementation and target validation will be required for this analysis to lead to new drug targets. The second task is to encourage the participation of medicinal chemists in this process of the identification and development of new drugs for parasitic diseases, increasingly recognised during the past decade. The participation of chemists has led to the identification of novel inhibitors for newly identified targets and interaction with biochemists in rational drug design. Pharmaceutical chemists have improved the bioavailability of both old and new drugs. The third task, associated with the absence of economic incentives, is the development of new drugs for parasitic diseases. The pharmaceutical industry has largely ignored parasitic diseases because the small financial return makes it difficult to even cover the costs of development. The current cost of bringing a drug to market is estimated at 250M ECUs. Of 1,223 new chemical entities registered between 1975-1996, less than 1% (11) were specifically indicated for tropical diseases. However, it is essential to involve the pharmaceutical companies in this search as only industry has the expertise and capacity to develop new drugs. Although the pharmaceutical industry has not played a full role in the process for sometime, in the past three years there have been significant efforts to involve the industry in the identification and development of new drugs for these diseases through:
(i) The setting up of a public-private partnership (PPP) for the development of new antimalarial drugs, the Medicines for Malaria Venture (MMV), that is supporting consortia involving academia and both large and small pharmaceutical companies. Other PPPs for new drugs for trypanosomiasis and leishmaniasis are being supported by the Gates Foundation
(ii) the involvement of small pharmaceutical companies in Europe and North America in the identification and evaluation of new antimalarials as they can generate small profits and a credible profile for these companies
(iii) a 5 year guarantee of production of existing drugs for trypanosomiasis, following pressure from MSF, from three pharmaceutical companies
(iv) an Orphan drug policy in Europe that has focused attention on the possibility of tax incentives to companies with research in tropical diseases
The proposed COST Action will act to bring together the new opportunities afforded by the rapid changes in biology, the involvement of chemists and the renewed participation of small and large pharmaceutical companies to focus upon the development of new anti-parasitic drugs.
The COST Action will form relevant links with EU initiatives (a) in pathogen genomics through already established contacts with the Plasmodium, Leishmania and Trypanosoma projects and (b) antimicrobial drugs, for example, EURONEAT and proposed Integrated Programmes. Contacts under the EU Framework programmes will ensure complementary, for example to the malaria vaccine platform, and that Co-ordinators of projects under the EU's 5th and 6th Framework Programmes on drug discovery and drug resistance are informed of the COST Action activities and invited to participate.
It is essential that the COST Action gives encouragement to scientists in Europe, from both academia and industry who have the expertise in biology, chemistry and drug development, to combine forces to play a full part in the development of new anti-parasitic drugs. An important aspect of this is access to the techniques involved in post-genomic research and information analysis, materials, skills and facilities. The process requires sustainability to ensure that a pipeline of new drugs for these diseases is in place, with due understanding of the high failure rate and the length of time it takes for new drugs to reach the clinic. However, unless action is taken now, we will be in the same situation in 10 years time.