Antiretroviral Drugs Inhibit Malaria Signal Peptide Peptidase
Okure, Carolyn.
2017
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Abstract: Malaria is listed on the CDC website1 as one of the more deadly diseases in the world today. According to the World Health Organization, the global disease burden for malaria in 2015 was at about 214 million new cases with the African region accounting for 88 percent of these cases2. Malaria is caused by a parasitic protozoan known as Plasmodium that grows and reproduces within the blood... read moreof its host organism after an initial multiplication stage in the liver. It is transmitted via a carrier organism, also known as a vector. The female Anopheles mosquito is responsible primarily for propagating the malaria parasite during pregnancy as she craves human blood. The malaria transmitting Anopheles mosquito is prevalent in regions prone to malaria. Upon completion of parasite differentiation within the mosquito gut, the parasite is carried in the mosquito saliva and transferred to its human host when a mosquito bite occurs. Once within the host, the parasite undergoes a series of developmental phases that involve two stages; the liver stage and the blood stage, the liver stage occurring first. In the liver stage multiplication occurs followed by maturation and growth, asexual reproduction and subsequent release of the parasite into the blood. Hibernation a process where parasites lie dormant within the hepatocytes for extended periods occurs during the liver stage. Parasite hibernation could last up to a year. In the blood stage red blood cells (RBCs) are invaded by parasites which grow, mature and reproduce asexually resulting in the continuation of the malaria life cycle. Differentiation and sexual reproduction occur also in this stage. While various species of the malaria parasite have been identified for multiple hosts, four species are common for infection in humans: P. falciparum, P. vivax, P. ovale, and P. malariae. The most lethal form being P. falciparum. Zoonotic infection by monkey P. knowlesi, is also common in certain parts of Asia and Africa. Considering the impending emergence of drug resistance and given the high morbidity and mortality caused by the most lethal malaria species P. falciparum, there arises an urgent need to develop new drugs and vaccines against malaria. Signal Peptide Peptidase (SPP) is a membrane-embedded enzyme that functions to cleave transmembrane proteins, primarily in the endoplasmic reticulum (ER) of cells, releasing them to participate in multiple signaling and regulatory activities. In P. falciparum, SPP plays a significant role in cleaving transmembrane substrates as a clearing mechanism to reduce ER stress within the parasite. This process is a key step in the survival and further development of the parasite within its host. Failure to cleave transmembrane proteins by P. falciparum SPP could result in parasite death due to ER stress. This key feature of P. falciparum Signal Peptide Peptidase (PfSPP) has made it an appealing target for pharmacological intervention. A number of antiretroviral drugs function as aspartic protease inhibitors. These drugs are known to inhibit the development of the Human Immunodeficiency Virus (HIV) in humans since the virus relies on aspartic proteases for survival3. In the present study, we tested the effects of aspartic protease inhibitors on malaria parasitized erythrocytes. Our results show that aspartic protease inhibitors inhibit PfSPP resulting in the death of intraerythrocytic malaria parasites. Aspartic protease inhibitors have therefore been identified as potent antimalarial drugs with the potential to be used in combination therapy against malaria.
Thesis (M.S.)--Tufts University, 2017.
Submitted to the Dept. of Pharmacology & Experimental Therapeutics.
Advisor: Athar Chishti.
Committee: Margery Beinfeld.
Keywords: Pharmacology, and Medicine.read less - ID:
- 4j03d953m
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