Cysteine Proteases of Human Malaria Parasites
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, esp
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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. Keywords Hemoglobinases • Drug resistance • Protein–protein interactions • Hot-spot • Hemoglobin binding domain • Refolding domain • Anti-malarial
K.C. Pandey (*) Host-Parasite Interaction Biology Group, Protein-Protein Interactions Unit, National Institute of Malaria Research, (ICMR), Sector 8, Dwarka, New Delhi, 110077, India e-mail: [email protected] S. Chakraborti and N.S. Dhalla (eds.), Proteases in Health and Disease, Advances in Biochemistry in Health and Disease 7, DOI 10.1007/978-1-4614-9233-7_8, © Springer Science+Business Media New York 2013
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Introduction
Evidence begin in the middle of the 1800s, Pasteur, Kotch and his co-workers had provided convincing evidence that microbes can cause disease, and identified disease causing agents, called parasites. The understanding of the malaria parasites begins in 1880 with the discovery of the parasites in the blood of malaria patients by Alphonse Laveran. Later, it was Ronald Ross, a surgeon in the Indian Medical Service, who showed that malaria was transmitted by the bite of an infected female mosquito [1]. After these land mark discoveries, there are lots of advancement to our understanding of the integrated interrelationship between malaria parasite and their host as well as parasite biology. R
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