Cysteine Proteases of Human Malaria Parasites

Abstract

There is an urgent need for new drugs against malaria, one of the most important infections of human which takes millions of lives annually. Cysteine protease inhibitors have demonstrated anti-malarial effects, and they are potential new drug targets, especially when current drugs are showing resistance. Falcipains and vivapains are best characterized cysteine proteases of P. falciparum and P. vivax, respectively. Using cysteine protease inhibitors and manipulating cysteine proteases specific genes have confirmed their roles in hemoglobin hydrolysis. In P. falciparum, falcipain-2 and falcipain-3 are major hemoglobinases that hydrolyzes human hemoglobin. Vivapain-2, vivapain-3 and vivapain-4 are important cysteine proteases of P. vivax, which shared a number of features with falcipain-2 and falcipain-3. Structural and biochemical analysis of falcipains and vivapains showed that they have specific domains for specific functions. These include trafficking domain, inhibitory domain, refolding domain and hemoglobin binding domain. Recent study also indicates the mechanism of auto-activation of falcipains, where salt bridges and hydrogen bonds between pro-mature domains play crucial role. Study indicates that cysteine and aspartic proteases work collaboratively to enhance the parasites’ ability to hydrolyze host erythrocyte hemoglobin. Recent advances in cysteine proteases biochemistry and the complexes of cysteine proteases with small and macromolecular inhibitors provide structural insight to facilitate the drug design. Therefore, giving due importance to the cysteine proteases, this chapter will focus the recent advancement in the field of cysteine proteases of human malaria parasite and prospects for exploitation as drug targets.