Molecular interactions of chaperones as a target for anti-malarial drug development

• Applicant: Professor Dr. Jude Marek Przyborski
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens ; Biochemistry ; Cell Biology
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 271495877

• Final Report Year: 2023

Final Report Abstract

Due to their complicated lifecycle which takes place in two different hosts, malaria parasites are subjected to highly variable environmental conditions. To enable them to survive and propogate in such changing times, the parasites use a system of chaperones that help to stabilise their own cellular biochemistry. These chaperones are likely to recruit a number of other co-chaperones and accessory proteins to help them carry out their function. The interaction between the various chaperones themselves, and with accessory proteins such as co-chaperones are highly likely to be essential for the parasites to survive and thus cause pathogenesis in the human host. As such, this system, and the proteins within it, are a potentially attractive target for drug-development. It was our aim, in this project, to identify such accessory factors, develop assays to monitor such interactions, and then apply such assays to find inhibitors which block such important interactions.

Publications

• Plasmodium falciparum Hep1 Is Required to Prevent the Self Aggregation of PfHsp70-3. PLOS ONE, 11(6), e0156446.
  Nyakundi, David O.; Vuko, Loyiso A. M.; Bentley, Stephen J.; Hoppe, Heinrich; Blatch, Gregory L. & Boshoff, Aileen
  
• (−)-Epigallocatechin-3-Gallate Inhibits the Chaperone Activity of Plasmodium falciparum Hsp70 Chaperones and Abrogates Their Association with Functional Partners. Molecules, 22(12), 2139.
  Zininga, Tawanda; Ramatsui, Lebogang; Makhado, Pertunia; Makumire, Stanley; Achilinou, Ikechukwu; Hoppe, Heinrich; Dirr, Heini & Shonhai, Addmore
  
• Proteomic analysis of exported chaperone/co-chaperone complexes of P. falciparum reveals an array of complex protein-protein interactions. Scientific Reports, 7(1).
  Zhang, Qi; Ma, Cheng; Oberli, Alexander; Zinz, Astrid; Engels, Sonja & Przyborski, Jude M.
  
• Partners in Mischief: Functional Networks of Heat Shock Proteins of Plasmodium falciparum and Their Influence on Parasite Virulence. Biomolecules, 9(7), 295.
  Daniyan, Michael O.; Przyborski, Jude M. & Shonhai, Addmore
  
• Proteomic analysis of Plasmodium falciparum histone deacetylase 1 complex proteins. Experimental Parasitology, 198, 7-16.
  Engel, Jessica A.; Norris, Emma L.; Gilson, Paul; Przyborski, Jude; Shonhai, Addmore; Blatch, Gregory L.; Skinner-Adams, Tina S.; Gorman, Jeffrey; Headlam, Madeleine & Andrews, Katherine T.
  
• Detection of the in vitro modulation of Plasmodium falciparum Arf1 by Sec7 and ArfGAP domains using a colorimetric plate-based assay. Scientific Reports, 10(1).
  Swart, Tarryn; Khan, Farrah D.; Ntlantsana, Apelele; Laming, Dustin; Veale, Clinton G. L.; Przyborski, Jude M.; Edkins, Adrienne L. & Hoppe, Heinrich C.
  
• Characterisation of a unique linker segment of the Plasmodium falciparum cytosol localised Hsp110 chaperone. International Journal of Biological Macromolecules, 180, 272-285.
  Chakafana, Graham; Mudau, Pertunia T.; Zininga, Tawanda & Shonhai, Addmore
  
• Introductory Chapter: The Importance of Heat Shock Proteins in Survival and Pathogenesis of the Malaria Parasite Plasmodium falciparum. Advances in Experimental Medicine and Biology, 1-9.
  Przyborski, Jude M.
  
• Supporting data on characterisation of linker switch mutants of Plasmodium falciparum heat shock protein 110 and canonical Hsp70. Data in Brief, 37, 107177.
  Chakafana, Graham; Mudau, Pertunia T.; Zininga, Tawanda & Shonhai, Addmore