The Apicomplexa are primitive, unicellular eukaryotes with a complex life cycle that involves a stage as a parasite in a diverse range of animals; for example lizards, birds or mammals. These protozoa share a common apical secretory apparatus that mediates movement and since it is involved in tissue or cell penetration is key to infection. Apicomplexan parasites are the causal agents for a range of important veterinary and human diseases [1
]. For example, Eimeria tennella
causes coccidiosis, a persistent and problematic disease in the poultry industry, while infection with Babesia
species, Theileria annulata
and T. parva
curtails productivity in cattle herds. Cryptosporidium parvum
is a water- and food-borne pathogen of livestock that also, like Babesia sp.
infects humans. Toxoplasma gondii
is a common parasite of cats that causes a mild disease in healthy humans but, like C. parvum
, T. gondii
becomes particularly problematic in immunocompromised individuals such as AIDS/HIV patients. The most important members of this family of parasites are the Plasmodium
species, which are responsible for malaria, a disease that continues to exact a devastating toll on human populations in the tropics [2
Vaccination would be an ideal method of dealing with these parasitic pathogens, and is especially appealing with respect to malaria. However, generous long term funding for malaria vaccine development has gained little reward. One reason is that Plasmodium spp.
infect and shelter from the immune system within host cells and display antigenic variation, in their membrane-bound surface proteins [3
]. This capability prolongs parasite circulation in the blood, increasing the likelihood of transmission and helps immune system evasion.
There are suitable drugs for some of these diseases but finances control what happens to infected animals or those at risk and it is often cheaper to cull than treat. In some parts of the world treatment is not even an option. With respect to human diseases then compounds such as pyrimethamine are used to treat toxoplasmosis and malaria, and the introduction of artemisinin a boon for control of malaria [4
]. However, issues that interfere with prevention and cure include the cost of goods and lack of healthcare infrastructure. The problem is compounded by the emergence of drug resistant forms of Plasmodium
], in part a consequence of inappropriate drug use. This means it is important to search out new treatments as one aspect of fighting malaria. In addition since approximately 10 % of emerging human diseases are due to parasites there is great encouragement to progress antiparasitic drug development [7
The discovery of our current arsenal of antimalarial drugs owes much to colonialism and warfare. Now, advances in a number of scientific disciplines means that we can now couple access to extensive genomic information on the apicomplexan protists [e.g. 8
], with improved understanding of their biology and of drug action. These data provide opportunities to apply medicinal chemistry approaches to modify known and successfully exploited chemical scaffolds to derive new drugs against already proven targets but in addition serve to map out potential new targets that might be exploited for structure based drug discovery [9
]. It is the later area that is of interest here.
The ideal drug target in a protozoan parasite is one that provides a biological function required for survival or infectivity, that is unique to the parasite and absent from the mammalian host or sufficiently divergent that species selective inhibition is possible. For practical reasons the types of molecules that are ultimately sought must be stable, orally bioavailable, and cheap to manufacture. The molecules should have high affinity for one or more targets in the parasite, kill the pathogen quickly and should present little or no toxicity against humans. Oral bioavailability is a priority since it provides the practical benefit of using tablets in developing countries, and optimizes chances of treating parasites occupying an intracellular niche or which infect the central nervous system. The Lipinski guidelines addressing issues of bioavailability [10
] are particularly relevant to antiparasite drug research. For protozoan parasites, drug research is influenced by the requirement for selectivity for one eukaryotic cell (the parasite) over another (the host) and in this respect the research is more similar to anticancer than antibacterial drug research.