Inhibition of Plasmepsin V Activity Demonstrates Its Essential Role in Protein Export, PfEMP1 Display, and Survival of Malaria Parasites

• DOI: 10.1371/journal.pbio.1001897
• Publication Date: 2014-07-01T21:09:42Z
• Authors: Brad E. Sleebs; Sash Lopaticki; Danushka S. Marapana; Matthew T. O'Neill; Pravin Rajasekaran; Michelle Gazdik; Svenja Günther; Lachlan W. Whitehead; Kym N. Lowes; Lea Barfod; Lars Hviid; Philip J. Shaw; Anthony N. Hodder; Brian J. Smith; Alan F. Cowman; Justin A. Boddey
• Keywords: 0301 basic medicine; 570; Cell biology; Aspartic Acid Proteases; Erythrocytes; QH301-705.5; Plasmodium falciparum; Immunology; Protozoan Proteins; Endoplasmic Reticulum; Microbiology; Gene; Biochemistry; 630; 03 medical and health sciences; Virology; Health Sciences; Parasite hosting; Aspartic Acid Endopeptidases; Humans; Biology (General); Global Impact of Arboviral Diseases; Biology; Sulfonamides; Gene knockdown; Virulence; FOS: Clinical medicine; Mechanisms of Multidrug Resistance in Cancer; Public Health, Environmental and Occupational Health; Computer science; Malaria; Protease; 3. Good health; World Wide Web; Protein Transport; Oncology; Enzyme; FOS: Biological sciences; Medicine; Plasmodium vivax; Oligopeptides; Apicomplexa; Research Article

The malaria parasite Plasmodium falciparum exports several hundred proteins into the infected erythrocyte that are involved in cellular remodeling and severe virulence. export mechanism involves element (PEXEL), which is a cleavage site for protease, Plasmepsin V (PMV). PMV gene refractory to deletion, suggesting it essential, but definitive proof lacking. Here, we generated PEXEL-mimetic inhibitor potently blocks activity of isolated from P. vivax. Assessment revealed PEXEL occurs cotranslationaly, similar signal peptidase. Treatment falciparum–infected erythrocytes with caused dose-dependent inhibition processing as well protein export, including impaired display major virulence adhesin, PfEMP1, on surface, cytoadherence. killed parasites at trophozoite stage knockdown enhanced sensitivity inhibitor, while overexpression increased resistance. This provides first direct evidence essential spp. survival human validates an antimalarial drug target.