oa Editorial [Hot Topic:Drug Targets for the Treatment of Protozoan Parasitic Diseases (Guest Editor: Luke Guddat)]

Infections caused by the invasion of protozoan parasites into human hosts represent one of the most serious public health problems in the world today with approximately one billion people living in areas of risk. Such diseases include: (i) malaria, caused by Plasmodium spp, with falciparum and vivax being the most lethal and prevalent species; (ii) visceral leishmaniasis caused by Leishmania donovani, infantum or chagasi (iii) sleeping sickness (Human African Trypanosomiasis) caused by Trypanosoma brucei; (iv) Chagas disease caused by Trypanosoma cruzi and; (v) schistosomiasis caused by Schistosoma spp. Malaria is the most well documented and is found in Africa, Central and South America and South-East Asia. Statistically malaria is the most lethal of the parasitic diseases with about 1-2 million deaths per year, but other protozoan parasites are also a major source of disease leading to morbidity and mortality. In terms of the number of reported infections, schistosomiasis and malaria are similar, though the number of deaths per annum due to malaria is higher. Schistosomiasis is endemic in more than 70 developing countries predominantly in Africa, with more than 200 million people are infected leading to ∼20,000 deaths per year. Sleeping sickness is reported to affect as many as 66 million people in sub-Saharan Africa accounting for ∼50,000 deaths per year, while 7.7 million currently have Chagas disease which is endemic in 21 countries in Latin and South America. It accounts for ∼20,000 deaths per year. Historically, treatment of parasitic infections has predominantly relied on the application of plant products. For example, the bark of the chinchona tree or the leaves of the herb, Artemisia annua have been used for the treatment of malaria. These natural remedies were discovered fortuitously rather than by sound scientific reasoning. This is highlighted by the fact that the active components were not identified until many centuries later (i.e. quinine and artemisinin). Only a few therapeutic agents have been developed by pharmaceutical companies (e.g. benznidazole by Hoffman-La Roche for Chagas disease and Praziquantel by Bayer and Merck for schistosomiasis). This is understandable given the cost of developing new molecular entities as drugs can be as high as US$1.8 billion. The fact that parasitic diseases are found predominantly in the developing world has contributed to the lack of new cost-effective drugs to reach the market. Pharmaceutical companies generally have not been presented with the financial incentives to support the research required to discover and develop therapies against new targets. However, though funding is still limited, philanthropic societies such as the Bill and Melinda Gates Foundation are providing much needed sources of revenue to take up the challenge of eradicating these diseases. Today, however, the chemical arsenal to treat each of the parasitic diseases is still limited to less than a handful of compounds. Furthermore, other granting bodies are recognizing the challenge and importance of the severe socio-economic burden caused by these diseases. They are also providing some of the much needed support as evidenced by the acknowledgements in this series of reviews. As a result, the over reliance on the use of older medications has resulted in resistance now being commonplace. To partially overcome or delay the on-set of resistance, the idea of combination therapies has been introduced. For example, it is now recommended by the World Health Organization that the artemisisins only be administered in combination with other antimalarial drugs such as mefloquine, lumefantrine, amodiaquine, piperaquine and the antifolates, all of which most likely target alternative metabolic pathways to that of the artemisisins. However, even this approach is also now failing because there are reports that artemisisin resistance to Plasmodium falciparum malaria has developed along the Cambodian-Thailand border. As a result there are now no drugs currently available to treat malaria for which resistant strains have not emerged. The need for new antiparasitic drugs is further highlighted by the fact that medications to treat diseases such as Chagas and sleeping sickness can be painful to administer and the side-effects can be extremely harmful. For example, Melasoprol and Eflornithine are the only two drugs currently available to treat second stage African sleeping sickness. Melasoprol is an arsenic derivative and therefore highly toxic while the dose regime for Eflornithine is strict and difficult to apply to patients. Thus, there is an urgent requirement to develop new antiparasitic therapies that have reduced toxic side effects, are cost-effective, easy to administer and for which resistance is less likely to occur. To identify new antiparasitic candidate drug leads a number of diverse approaches can be adopted. These include random screening using the vast libraries of compound extracted from plants, venoms and other natural sources or the use of chemical libraries synthesized in pharmaceutical companies. However, ultimately the process of drug discovery will need to encompass a fundamental understanding of the biology of the organism and the chemistry of the drug if new therapeutics are to be developed to their maximum potential. Such new drugs should decrease significantly the ability of the parasite to mutate to develop resistance. The objective of this edition of “Current Topics in Medicinal Chemistry” is to indentify promising new antiparasitic drug leads, their targets and the progress that has been made to advance these leads towards developing new pharmaceuticals. Given that protozoan parasites have evolved with different biological characteristics the likelihood of the discovery of a general antiparasitic drug is remote. Nonetheless, some protozoan parasites do posses similar metabolic pathways and physical characteristics, thus it is plausible that drugs that successfully target one parasitic organism may also be effective in other parasites. For example (there are many others), pyrimethamine, a drug that inhibits dihydrofolate reductase, can be used to treat both malaria and immunocompromised patients infected by Toxoplasma gondi. This review therefore offers the opportunity for the potential integration of drug lead data that may have arisen through the studies of one pathogenic organism to be translated into drug lead data for an alternate organism....