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Image Developing New Antimalarial Drugs That Block Protein Trafficking (1)

Discovering novel antimalarials to block parasite virulence

Past project

Drugs are the main weapons used to combat malaria infection, but parasites are becoming resistant and new medicines and drug targets are needed. One potential target is the protein trafficking pathways parasites and PTEX machine used to deliver proteins within their own cells and the human red blood cells the parasites infect. If the protein trafficking system could be blocked this would kill the parasites and eliminate malaria.

Objective

We aim to understand the biology underpinning malaria parasite virulence and use this knowledge to aid our discovery and development of novel antimalarials that reduce the parasites’ ability to harm its human host. 

Approach

We perform a range of biochemical, cell biological and plate-based assays to understand basic parasite biology and virulence. We have developed a novel luminescence-based screening platform to discover novel antimalarials that target parasite components that are essential for parasite survival.

Community impact

Better, safer, and cheaper antimalarial drugs would benefit endemic communities around the world and could accelerate malaria elimination. The research will also provide new knowledge about parasite biology that could inform future treatment options.

Research and reports

05 Nov 2023

Sequence elements within the PEXEL motif and its downstream region modulate PTEX-dependent protein export in Plasmodium falciparum.

Gabriela M, Barnes CBG, Leong D, Sleebs BE, Schneider MP, Littler DR, Crabb BS, de Koning-Ward TF, Gilson PR

31 Jul 2023

PTEX helps efficiently traffic haemoglobinases to the food vacuole in Plasmodium falciparum.

PLoS pathogens

Jonsdottir TK, Elsworth B, Cobbold S, Gabriela M, Ploeger E, Parkyn Schneider M, Charnaud SC, Dans MG, McConville M, Bullen HE

29 Jun 2023

The delayed bloodstream clearance of Plasmodium falciparum parasites after M5717 treatment is attributable to the inability to modify their red blood cell hosts.

Frontiers in cellular and infection microbiology

Schneider MP, Looker O, Rebelo M, Khoury DS, Dixon MWA, Oeuvray C, Crabb BS, McCarthy J, Gilson PR

28 Aug 2023

A Pyridyl-Furan Series Developed from the Open Global Health Library Block Red Blood Cell Invasion and Protein Trafficking in Plasmodium falciparum through Potential Inhibition of the Parasite's PI4KIIIB Enzyme.

ACS infectious diseases

Ling DB, Nguyen W, Looker O, Razook Z, McCann K, Barry AE, Scheurer C, Wittlin S, Famodimu MT, Delves MJ

22 Feb 2022

A revised mechanism for how Plasmodium falciparum recruits and exports proteins into its erythrocytic host cell.

PLoS pathogens

Gabriela M, Matthews KM, Boshoven C, Kouskousis B, Jonsdottir TK, Bullen HE, Modak J, Steer DL, Sleebs BE, Crabb BS

25 Apr 2022

The Plasmodium falciparum parasitophorous vacuole protein P113 interacts with the parasite protein export machinery and maintains normal vacuole architecture.

Molecular microbiology

Bullen HE, Sanders PR, Dans MG, Jonsdottir TK, Riglar DT, Looker O, Palmer CS, Kouskousis B, Charnaud SC, Triglia T

15 Aug 2022

The Medicines for Malaria Venture Malaria Box contains inhibitors of protein secretion in Plasmodium falciparum blood stage parasites.

Traffic (Copenhagen, Denmark)

Looker O, Dans MG, Bullen HE, Sleebs BE, Crabb BS, Gilson PR

03 May 2021

Characterisation of complexes formed by parasite proteins exported into the host cell compartment of Plasmodium falciparum infected red blood cells.

Cellular microbiology

Jonsdottir TK, Counihan NA, Modak JK, Kouskousis B, Sanders PR, Gabriela M, Bullen HE, Crabb BS, de Koning-Ward TF, Gilson PR

10 May 2021

Defining the Essential Exportome of the Malaria Parasite.

Trends in parasitology

Jonsdottir TK, Gabriela M, Crabb BS, F de Koning-Ward T, Gilson PR

28 Sep 2021

The Role of Malaria Parasite Heat Shock Proteins in Protein Trafficking and Remodelling of Red Blood Cells.

Advances in experimental medicine and biology

Jonsdottir TK, Gabriela M, Gilson PR

03 Apr 2019

The N-terminus of EXP2 forms the membrane-associated pore of the protein exporting translocon PTEX in Plasmodium falciparum.

Journal of biochemistry

Sanders PR, Dickerman BK, Charnaud SC, Ramsland PA, Crabb BS, Gilson PR

20 Apr 2018

The malaria PTEX component PTEX88 interacts most closely with HSP101 at the host-parasite interface.

The FEBS journal

Chisholm SA, Kalanon M, Nebl T, Sanders PR, Matthews KM, Dickerman BK, Gilson PR, de Koning-Ward TF

23 May 2018

Spatial organization of protein export in malaria parasite blood stages.

Traffic (Copenhagen, Denmark)

Charnaud SC, Jonsdottir TK, Sanders PR, Bullen HE, Dickerman BK, Kouskousis B, Palmer CS, Pietrzak HM, Laumaea AE, Erazo AB

20 Aug 2018

Plasmepsin V cleaves malaria effector proteins in a distinct endoplasmic reticulum translocation interactome for export to the erythrocyte.

Nature microbiology

Marapana DS, Dagley LF, Sandow JJ, Nebl T, Triglia T, Pasternak M, Dickerman BK, Crabb BS, Gilson PR, Webb AI

15 Nov 2018

Knockdown of the translocon protein EXP2 in Plasmodium falciparum reduces growth and protein export.

PloS one

Charnaud SC, Kumarasingha R, Bullen HE, Crabb BS, Gilson PR

Partners

Funding partners

National Health and Medical Research Council (NHMRC)

Collaborators

  • Deakin University
  • WEHI
  • Deakin University
  • Monash University

Project team

Professor Brendan Crabb AC

Professor Brendan Crabb AC

Director and CEO; Chair Australian Global Health Alliance and Chair Pacific Friends of Global Health
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Associate Professor Paul Gilson

Associate Professor Paul Gilson

Deputy Discipline Head, Life Sciences; Co-Head, Malaria Virulence and Drug Discovery Group; Head of Burnet Cell Imaging Facility
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Claudia Barnes

Claudia Barnes

Research Assistant
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Dr Hayley Bullen

Dr Hayley Bullen

Co-Head, Malaria Virulence and Drug Discovery Group
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Dr Oliver Looker

Dr Oliver Looker

Postdoctoral Scientist
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Molly Schneider

Molly Schneider

Research Assistant
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