The Medicines for Malaria Venture Malaria Box contains inhibitors of protein secretion in Plasmodium falciparum blood stage parasites
Details
Publication Year 2022-09,Volume 23,Issue #9,Page 442-461
Journal Title
Traffic
Abstract
Plasmodium falciparum parasites which cause malaria, traffic hundreds of proteins into the red blood cells (RBCs) they infect. These exported proteins remodel their RBCs enabling host immune evasion through processes such as cytoadherence that greatly assist parasite survival. As resistance to all current antimalarial compounds is rising new compounds need to be identified and those that could inhibit parasite protein secretion and export would both rapidly reduce parasite virulence and ultimately lead to parasite death. To identify compounds that inhibit protein export we used transgenic parasites expressing an exported nanoluciferase reporter to screen the Medicines for Malaria Venture Malaria Box of 400 antimalarial compounds with mostly unknown targets. The most potent inhibitor identified in this screen was MMV396797 whose application led to export inhibition of both the reporter and endogenous exported proteins. MMV396797 mediated blockage of protein export and slowed the rigidification and cytoadherence of infected RBCs-modifications which are both mediated by parasite-derived exported proteins. Overall, we have identified a new protein export inhibitor in P. falciparum whose target though unknown, could be developed into a future antimalarial that rapidly inhibits parasite virulence before eliminating parasites from the host.
Publisher
Wiley
Keywords
Animals; *Antimalarials/metabolism/pharmacology/therapeutic use; Erythrocytes/parasitology; Humans; *Malaria; *Malaria, Falciparum/drug therapy/parasitology; *Parasites/metabolism; Plasmodium falciparum/metabolism; Protozoan Proteins/metabolism; Plasmodium falciparum; antimalarials; malaria; protein transport; small molecule libraries
WEHI Research Division(s)
Chemical Biology
PubMed ID
36040075/
Open Access at Publisher's Site
https://doi.org/10.1111/tra.12862
NHMRC Grants
NHMRC/1092789
Terms of Use/Rights Notice
Refer to copyright notice on published article.


Creation Date: 2022-09-07 09:51:00
Last Modified: 2022-09-07 10:03:00
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