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

Heat shock protein 70 (Hsp70) and Hsp90 are some of the most studied molecular chaperones, proteins which themselves are responsible for the folding of other proteins in the cell. Hsp70 binds non-native proteins whilst substrates of Hsp90 are usually in native-like forms. Proteins that require both Hsp70 and Hsp90 to fold are thus transferred from Hsp70 to Hsp90 during the folding process. Eukaryotic Hsp90 participates in the conformational regulation of signal transduction molecules, such as tyrosine kinases and steroid hormone receptors. For example, steroid hormone receptors associate with Hsp90 in order for them to adopt conformational competence for hormone binding. In addition to Hsp70 and Hsp90, there are numerous co-chaperones and other protein interactors which are essential for the efficient functioning of the chaperone system and thus efficient protein homeostasis. We have previously characterised a P. falciparum homologue of the Hsp70-Hsp90 Organising Protein (PfHop) and analysed its interaction with parasite encoded chaperones. In the previous funding period we were interested in understanding the interaction between PfHop and PfHsp70-1/PfHsp90 with a view to blocking this interaction. Additionally, we wished to establish protein:protein interaction assays for use in drug-screening. In this renewal proposal we propose to continue our analysis of chaperone/co-chaperone interactions in the P. falciparum system, now including one further molecular interactor, PfHsp70-z. Additionally, we shall now use our previously established interaction assays to screen libraries for compounds which block this likely essential molecular interaction.

• DFG Programme: Research Grants
• International Connection: South Africa
• Co-Investigators: Dr. Adelle Burger, Ph.D.; Professor Dr. Klaus Lingelbach (†)
• International Co-Applicants: Professor Dr. Heinrich Carl Hoppe; Professor Dr. Addmore Shonhai, Ph.D.