Charlie Saunders

Next generation probes for protein-protein interactions: exploring the function and druggability of motor complexes in the malaria parasite

Charlie Saunders - Writing up


Analysis and manipulation of protein-protein interactions (PPIs) is one of the emerging frontiers of chemical biology where the design, synthesis and application of chemical probes to target specific interactions can have a transformative impact for research into biological tools and ultimately new drugs. However, in many cases, the extent of our understanding of the role and potential druggability of a given PPI is largely constrained by whether a chemical probe is available for that PPI. Despite substantial investment in development of PPI inhibitors, direct disruption of most such interactions remains an unsolved problem. Here we will adopt a conceptually different approach: development of probes that can manipulate a specific PPI via redistribution of a protein between existing complexes, redirecting a protein to form a new PPI with a novel function, alter the subcellular localisation of a protein complex, or add new (unnatural) chemistry to a PPI to directly alter how the complex behaves in response to a stimulus (such as photoactivation, phosphorylation, etc.). To maximise impact and breadth of applicability, these probes must function in the context of a complex living organism, on endogenous, wild-type systems. The technologies we will use build directly on the outputs of two highly successful ICB projects on the host cell invasion motor complex (Tate/Cota/Holder) and on protein lipidation (Tate) in the malaria parasite Plasmodium falciparum, and will leverage unique and powerful microscopy-based assays for parasite shape and motility (Baum). We will develop probes to manipulate selectively the multiple and functionally diverse actomyosin motor complexes used by malaria parasites for different forms of motility and host cell invasion, providing proof-of-concept for manipulation of PPIs and new insights into the distinct roles and potential druggability of these motors.