Journal article

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

Brad E Sleebs, Sash Lopaticki, Danushka S Marapana, Matthew T O'Neill, Pravin Rajasekaran, Michelle Gazdik, Svenja Guenther, 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

PLoS Biology | PUBLIC LIBRARY SCIENCE | Published : 2014

Abstract

The malaria parasite Plasmodium falciparum exports several hundred proteins into the infected erythrocyte that are involved in cellular remodeling and severe virulence. The export mechanism involves the Plasmodium export element (PEXEL), which is a cleavage site for the parasite protease, Plasmepsin V (PMV). The PMV gene is refractory to deletion, suggesting it is essential, but definitive proof is lacking. Here, we generated a PEXEL-mimetic inhibitor that potently blocks the activity of PMV isolated from P. falciparum and Plasmodium vivax. Assessment of PMV activity in P. falciparum revealed PEXEL cleavage occurs cotranslationaly, similar to signal peptidase. Treatment of P. falciparum-infe..

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Grants

Awarded by NHMRC


Awarded by Human Frontiers Science Program


Awarded by Ramaciotti Foundation Establishment Grant


Awarded by CASS Foundation Science and Medicine grant


Awarded by CPM/NSTDA


Funding Acknowledgements

This work was supported by an NHMRC Project Grant (1010326 to JAB), the Human Frontiers Science Program (RGY0073/2012 to JAB), a Ramaciotti Foundation Establishment Grant (3197/2010 to JAB), a CASS Foundation Science and Medicine grant (SM.12.4348 to JAB), the Australian Cancer Research Foundation, and a Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. PJS acknowledges CPM/NSTDA grant P-11-00673. AFC is a Howard Hughes International Scholar and JAB is a QEII Fellow of the Australian Research Council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.