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A multistage antimalarial targets the plasmepsins IX and X essential for invasion and egress

Paco Pino1, Reto Caldelari2, Budhaditya Mukherjee3

  • 1Department of Microbiology and Molecular Medicine, Faculty of Medicine-University of Geneva, Centre Médical Universitaire (CMU), 1211 Geneva, Switzerland. paco.pino@unige.ch dominique.soldati-favre@unige.ch.

Science (New York, N.Y.)
|October 28, 2017
PubMed

Insights

A novel compound, 49c, inhibits key proteases (plasmepsins IX and X) essential for malaria parasite invasion and egress. This multistage antiplasmodial activity offers a potential new therapeutic strategy against malaria.

Area of Science:

  • Malariology
  • Parasitology
  • Protease Inhibitor Drug Discovery

Background:

  • Regulated exocytosis of secretory organelles is critical for malaria parasite (Plasmodium) invasion and egress.
  • Many Plasmodium effector proteins undergo essential proteolytic processing before and after exocytosis.

Purpose of the Study:

  • To investigate the antiplasmodial activity of a novel hydroxyl-ethyl-amine-based scaffold compound, 49c.
  • To determine if compound 49c targets proteases involved in preexocytosis processing of Plasmodium secretory proteins.

Main Methods:

  • Assessed the multistage antiplasmodial activity of compound 49c.
  • Investigated compound 49c's inhibition of plasmepsins IX (PMIX) and X (PMX) activity.
  • Utilized conditional gene excision to study the role of PMIX in parasite invasion.

Main Results:

  • Compound 49c demonstrated multistage antiplasmodial activity.
  • Compound 49c inhibits preexocytosis processing of rhoptry and microneme proteins by targeting PMIX and PMX.
  • Conditional excision of PMIX confirmed its essential role in parasite invasion.
  • Recombinant PMIX and PMX were shown to cleave invasion and egress factors in a manner sensitive to compound 49c.

Conclusions:

  • Compound 49c is a potent inhibitor of PMIX and PMX, crucial aspartic proteases in Plasmodium.
  • Targeting PMIX and PMX with inhibitors like 49c represents a promising strategy for developing new anti-malarial drugs.
  • The study highlights the importance of preexocytosis protein processing for malaria parasite infectivity.

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