Human malaria, caused the protozoan parasite Plasmodium, remains to be one of the most deadly diseases and poses serious public health problem. The treatment of the disease is complicated by development of resistance in the parasite against drugs that were effective previously. There is urgent need for discovering new and affordable chemotherapeutic agents for treatment of malaria. The parasite undergoes a complex series of developmental changes in its hosts, mosquito and human, but the asexual reproductive cycle in erythrocytes is associated with disease symptoms. Of the four strains that cause human malaria, P. falciparum is the most lethal.

In order to apply the rational drug design approach to develop anti-malarial agents it is necessary to identify biochemical steps indispensable for the parasite, discover compounds that block the activity of the enzyme regulating the reaction in the parasite but does not affect the host enzyme significantly.

Glycolytic pathway of malaria parasite offer attractive targets

The intraerythrocytic stage of malaria does not store glycogen or other reserve polysaccharide. Consequently, simple sugars are essential for continued growth and reproduction of the plasmodia. Glucose consumption in malaria infected erythrocytes, increases significantly, reaching 50 to 100-fold higher as compared to uninfected red cells. The lack of a functional tricarboxylic acid cycle gives the glycolytic pathway elevated importance in malaria parasite. A complete set of it’s own glycolytic enzymes are present in Plasmodia and certain parasite enzymes increase markedly in parasitized human red cells, the largest percentage increases seen with hexokinase, enolase and pyruvate kinase. Several parasite enzymes have low sequence identity to the equivalent host enzyme. Together, these information suggest that blocking the glylcolytic pathway of the parasite could be deadly for the parasite and interference with the main energy production mechanism of the parasite may be possible without severely affecting the host enzymes. Crystal structure of PfLDH and aldolase (fructose-1, 6-biphosphate aldolase) revealed that parasitic enzymes possess structural features that distinguish them from the mammalian form. Glycolytic enzymes have also been targets for designing drugs against other diseases.

One of the ways to overcome the problem of resistance against a particular drug is to apply a cocktail of multiple drugs that act on different enzymes. A research program in our laboratory focuses on the structure function analysis of glycolytic enzymes of P. falciparum. An ongoing project focuses on the identification of novel inhibitors of PfLDH using high throughput screening of a combinatorial library and structure guided drug design. We have recently determined the crystal structure of the 3-phosphoglycerate kinase enzyme of P. falciparum.