Drug Design Targeting Parasites

Although any microbe that infects a human (virus, bacteria, fungus, etc.) could theoretically be considered to be a parasite, the term parasite tends to be reserved for three types of infectious agents protozoa, helminths, and arthropods. These may be subdivided as follows  

Giardia (causing giardiasis—cramps, diarrhea, nausea) 

Entamoeba (causing amebiasis— potentially life-threatening dysentery) 

Plasmodium (causing malaria—high fever, sweating, headache, nausea) 

Balantidium (causing balantidiasis—diarrhea, dysentery, ulcers) 

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Since mitochondria are energy factories, they are essential to cellular life. This fact can be usefully exploited in drug design to enable selective killing of unwanted cell types. For example, the mitochondria of certain parasites are fundamentally different from those of the host human cells. Accordingly, it is possible to selectively kill such parasites by targeting the biochemical uniqueness of their mitochondria. Certain 4-hydroxyquinoline derivatives are effective antiparasitic agents that use this mechanism. 

Figure 9.5 Malaria parasites have a complex life cycle, existing in many different forms between humans and mosquitoes. This offers a number of targets for drug design.

A few other less studied biochemical approaches such as purine and pyrimidine metabolism protein biosynthesis and lipid metabohsm in helminths also provide targets for antiparasitic drug design [83]. Like protozoal parasites, some helminths such as S. mansoni (adult and larval forms) lack de novo purine biosynthesis and, therefore, depend entirely on the salvage mechanism for their purine requirements. Similarly amino acid metabolism and biosynthesis of proteins has also been not worked out in many parasites [83a]. Although the helminths meet their requirements of amino acids by absorbing freely from the host, they may also synthesize some amino acids. For example. Fasciola hepatica, schistosomes and other trematodes produce proline by a reaction sequence given in Chart 8. Similarly H. diminuta can... 

Perez-Montfort, R. The interfaces of oligomeric proteins as targets for drug design against enzymes from parasites Curr. Top. Med. Chem. 2002, 2,457... 

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