Abstract
The purpose of this study was to investigate the blood stage of the malaria causing parasite, Plasmodium falciparum, to predict potential protein interactions between the parasite merozoite and the host erythrocyte and design peptides that could interrupt these predicted interactions. We screened the P. falciparum and human proteomes for computationally predicted short linear motifs (SLiMs) in cytoplasmic portions of transmembrane proteins that could play roles in the invasion of the erythrocyte by the merozoite, an essential step in malarial pathogenesis. We tested thirteen peptides predicted to contain SLiMs, twelve of them palmitoylated to enhance membrane targeting, and found three that blocked parasite growth in culture by inhibiting the initiation of new infections in erythrocytes. Scrambled peptides for two of the most promising peptides suggested that their activity may be reflective of amino acid properties, in particular, positive charge. However, one peptide showed effects which were stronger than those of scrambled peptides. This was derived from human red blood cell glycophorin-B. We concluded that proteome-wide computational screening of the intracellular regions of both host and pathogen adhesion proteins provides potential lead peptides for the development of anti-malarial compounds.
Highlights
Malaria was the underlying cause of death for 1.24 million people in 2010, the vast majority of these deaths were in Africa and can be attributed to the parasite causing the most virulent form of malaria in humans, P. falciparum [1]
The second set of proteins which we examined were P. falciparum proteins that are potentially involved in the invasion of the erythrocyte by P. falciparum [3]
We selected 13 computationally predicted peptides from three sources: (i) the whole P. falciparum proteome, (ii) P. falciparum proteins potentially involved in erythrocyte invasion and (iii) human erythrocytic proteins potentially involved in invasion
Summary
Malaria was the underlying cause of death for 1.24 million people in 2010, the vast majority of these deaths were in Africa and can be attributed to the parasite causing the most virulent form of malaria in humans, P. falciparum [1]. P. falciparum has an extremely complex life cycle that involves different cells and organ systems in both the female Anopheles mosquito and human host. When the mosquito bites the human host, P. falciparum sporozoites present in the PLOS ONE | DOI:10.1371/journal.pone.0127383. When the mosquito bites the human host, P. falciparum sporozoites present in the PLOS ONE | DOI:10.1371/journal.pone.0127383 June 3, 2015
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