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 b... read morelood of 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
- Component ID:
- tufts:22756
- To Cite:
- DCA Citation Guide EndNote
