One of the major goals of this project is to exploit model organisms (yeasts and higher eukaryotes) amenable to chemical/genetic techniques to dissect disease-related signalling pathways and pathophysiology.
A second theme is to support clever, dedicated and novel screening approaches, often based on synthetic biology or genetic interactions, to furnish novel reagents for the study of signalling pathways involved in, for example: modulation of lipid metabolism in Niemann-Pick C disease, protein palmitoylation, TOR signalling, or, response to hypoxia. The availability of pathway inhibitors, orphan or otherwise, provides the opportunity to probe, at a system-wide level, the temporally defined cellular consequences of perturbation of these pathways. These system-level studies, including Mass Spectrometry-based Quantitative ‘omics approaches, are supported by innovative chemistry, exploiting, for example, isotopically labelled probes, which greatly facilitates quantification of proteins, lipids and other metabolites.
A third and increasingly more prominent aspect of this project is the development of generic approaches to identify the molecular targets of orphan compounds. These compounds range from natural products used in traditional medicine to hits that come out in our screening efforts described above. Here too, we rely on innovative chemistry, exploiting for example novel “warheads” to selectively enrich particular classes of proteins. One such warhead contains a hypervalent Iodine moiety that efficiently labels thousands of proteins containing reactive cysteines, residues often targeted by small molecule inhibitors. Target identification is often rate limiting in drug screening campaigns and we are gearing up to meet this important challenge.