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

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
DOI: 10.1371/journal.pbio.1001897 Publication Date: 2014-07-01T21:09:42Z
ABSTRACT
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.
SUPPLEMENTAL MATERIAL
Coming soon ....
REFERENCES (47)
CITATIONS (126)