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
AUTHORS (16)
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.
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CITATIONS (126)
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