Structural biology and therapeutic targeting of proteins involved in infection and immunity (2016–2020)
The central objective of my work in the next five years will be to use structural biology approaches to advance the understanding of the function of proteins and protein complexes of medical relevance, particularly those involved in the processes of infection and immunity. This work will further form a foundation for therapeutic strategies, which will become an increased focus of my research. The two main research themes will involve proteins involved in bacterial pathogenesis and proteins involved in innate immunity pathways. Bacterial infections are responsible for over 10 million deaths per year. My work will focus on virulence factors from Streptococcus pneumoniae, Group A Streptococcus, Haemophilus influenzae and Neisseria meningitides. Examples include proteins involved in metal transport, GAS surface proteins, cholesterol-dependent cytolysins and proteins involved in capsule biosynthesis. Toll-like receptor (TLR)-associated innate immunity pathways are linked to infectious, autoimmune, inflammatory, cardiovascular and cancer-related disorders. We will target cytoplasmic TLR adaptor proteins MyD88, MAL, TRIF, TRAM and SARM and their binding partners. We have recently observed that these proteins signal through a higher-order assembly mechanism of the TIR (Toll/interleukin-1 receptor) domains, and will characterize this mechanism using an inter-disciplinary approach. We will also investigate redox regulation of MAL adaptor protein, and explore the function of SAM domains in the adaptor SARM. Additional projects in the laboratory will involve the characterization of anti-fungal and anti-viral drug targets and the development of bioinformatics tools. We have already developed lead molecules against bacterial, fungal and innate immunity targets, and will develop these into potential therapeutic agents.