title: Host cell remodelling in malaria parasites: a new pool of potential drug targets.
abstract: When in their human hosts, malaria parasites spend most of their time housed within vacuoles inside erythrocytes and hepatocytes. The parasites extensively modify their host cells to obtain nutrients, prevent host cell breakdown and avoid the immune system. To perform these modifications, malaria parasites export hundreds of effector proteins into their host cells and this process is best understood in the most lethal species to infect humans, Plasmodium falciparum. The effector proteins are synthesized within the parasite and following a proteolytic cleavage event in the endoplasmic reticulum and sorting of mature proteins into the correct vesicular trafficking pathway, they are transported to the parasite surface and released into the vacuole. The effector proteins are then unfolded before extrusion across the vacuole membrane by a unique translocon complex called Plasmodium translocon of exported proteins. After gaining access to the erythrocyte cytoplasm many effector proteins continue their journey to the erythrocyte surface by utilising various membranous structures established by the parasite. This complex trafficking pathway and a large number of the effector proteins are unique to Plasmodium parasites. This pathway could, therefore, be developed as new drug targets given that protein export and the functional role of these proteins are essential for parasite survival. This review explores known and potential drug targetable steps in the protein export pathway and strategies for discovering novel drug targets.
authors.affiliation: Burnet Institute, Melbourne, Victoria, Australia; Monash University, Melbourne, Victoria, Australia. Electronic address: gilson@burnet.edu.au.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gilson
authors.affiliation: Deakin University, Waurn Ponds, Victoria, Australia.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Chisholm
authors.affiliation: Burnet Institute, Melbourne, Victoria, Australia; Monash University, Melbourne, Victoria, Australia; University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Brendan S
authors.initials: BS
authors.lastname: Crabb
authors.affiliation: Deakin University, Waurn Ponds, Victoria, Australia.
authors.forename: Tania F
authors.initials: TF
authors.lastname: de Koning-Ward
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D015195:Drug Design; D004912:Erythrocytes / Q000469:parasitology* / Q000473:pathology; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology* / Q000473:pathology*; D058990:Molecular Targeted Therapy; D010963:Plasmodium falciparum / Q000502:physiology*
chemical_list: D000962:Antimalarials
keywords: Host cell modification; Malaria; Plasmodium falciparum; Protein export; Translocon; Virulence