Poster Presentation First Malaria World Congress 2018

Characterization of Plasmepsin X as a Cross-species Antimalarial Target (#436)

Kaiyuan Guo 1 , Brad Sleebs 1 , Alan Cowman 1 , Wai-Hong Tham 1
  1. Walter & Eliza Hall Institute, North Melbourne, VICTORIA, Australia

The emergence and spread of drug resistance have hindered the campaign for malaria eradication. The development of new drug targets is a critical addition to our anti-malarial arsenal. Plasmepsins, which are aspartic proteases expressed by malaria parasites, serve important functions for parasite survival. Among the 10 members of this enzyme family, plasmepsin X (PMX) is essential for P. falciparum growth and has been shown to be involved in the egress of merozoites from infected red blood cells and the invasion of merozoites into red blood cells [1, 2]. Several aspartic protease inhibitors, including peptidomimetic substrate competitive inhibitors 49c [3] and 1SR [4], possess anti-malarial activity against P. falciparum and are shown to target PfPMX.


Here we describe an adapted parasite growth assay and show that 49c and 1SR affect P. knowlesi and P. falciparum in a similar manner. We will further investigate whether PMX is a cross-species target for antimalarial development. Using parasite growth assays and a ligand processing assay, we will determine how these PMX inhibitors affect P. knowlesi during parasite growth and examine the molecular mechanisms for plasmepsin inhibition.

  1. Pino, P., et al., A multistage antimalarial targets the plasmepsins IX and X essential for invasion and egress. Science, 2017. 358(6362): p. 522-528.
  2. Nasamu, A.S., et al., Plasmepsins IX and X are essential and druggable mediators of malaria parasite egress and invasion. Science, 2017. 358(6362): p. 518-522.
  3. Ciana, C.-L., et al., Novel in vivo active anti-malarials based on a hydroxy-ethyl-amine scaffold. Bioorganic & medicinal chemistry letters, 2013. 23(3): p. 658-662.
  4. Jaudzems, K., et al., Plasmepsin inhibitory activity and structure-guided optimization of a potent hydroxyethylamine-based antimalarial hit. ACS medicinal chemistry letters, 2014. 5(4): p. 373-377.