Centenary celebrations article

Abstract

There is an urgent need for new drugs against malaria, which takes millions of lives annually. Cysteine proteases are potential new drug targets, especially when current drugs are showing resistance. Falcipains and vivapains are well characterized cysteine proteases of P. falciparum and P. vivax, respectively. Studies with cysteine protease inhibitors and manipulating cysteine proteases specific genes have suggested their roles in hemoglobin hydrolysis. In P. falciparum, falcipain-2 and falcipain-3 are major hemoglobinases that hydrolyze host erythrocyte hemoglobin in the parasite food vacuole. It is confirmed that disruption of the falcipain-2 gene led to a transient block in hemoglobin hydrolysis, and disruption of falcipain-3 gene was not possible, suggesting that protease is essential for erythrocytic parasites. On the other hand, 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. A recent study indicates that vivapains and aspartic protease of P. vivax works collaboratively to enhance the parasites' ability to hydrolyze host erythrocyte hemoglobin. Studies also indicate that falcipains and vivapains also hydrolyse the erythrocyte cytoskeleton proteins and involved in rupture of red blood cell. Structural and biochemical analysis of falcipains and vivapains showed that they have unique domains for specific functions. Overall, 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 review will briefly focus the recent advancement in the field of cysteine proteases of human malaria parasites.

Structural Insights Into Key Plasmodium Proteases as Therapeutic Drug Targets

“…FPs possess some unique structural domains as compared to other papain-like cysteine proteases. The N-terminal part of the prodomain functions in trafficking of FPs to the food vacuole and the C-terminal part of prodomain acts as an inhibitor of the mature domain, like other cysteine proteases of the C1 family ( Pandey, 2011 ). However, FPs possess short N-terminal extensions (about 12 aa) of the mature domain which is critical for folding of the mature domain to active enzyme ( Figure 5 ).…”

Protease Inhibitors from Marine Venomous Animals and Their Counterparts in Terrestrial Venomous Animals

“…Cysteine protease inhibitors have been proposed as antimalarial drugs, because of the critical role for these proteases in hemoglobin hydrolysis at the trophozoite stage of malaria parasite [197]. These proteases also take part in many human physiological pathways such as antigen processing and prohormone activation, as in some diseases including arthritis, Alzheimer’s disease, and cancer-cell invasion, reinforcing the importance of finding new cysteine protease inhibitors.…”

Cross-Talk between Malarial Cysteine Proteases and Falstatin: The BC Loop as a Hot-Spot Target

“…Among falcipain family cysteine proteases, key enzymes in erythrocytic parasites appear to be falcipain-2 (FP2) and falcipain-3 (FP3), which are major hemoglobinases of P. falciparum , and in P. vivax , vivapain-2 (VP2), vivapain-3 (VP3) and vivapain-4 (VP4) [4] . Structural and biochemical analysis of falcipains showed that they have specific domains with defined functions.…”