description
- Viral infections are responsible for an unquantifiable amount of disease, death and socioeconomic burden around the world. Some viruses seem too evasive to vaccinate against and antiviral drugs ultimately fail because they cause resistance in their viral targets. There is an urgent need for new classes of antiviral medicines. The main objective of my research proposal is to fast-track the development of 'host-directed therapies', a promising alternative to antiviral drugs that target viral proteins. To do this, I first want to understand which are the relevant participants of a host cell's response to viral infection. A frequently held assumption is that cells regulate their enzymes simply by changing their relative abundance. We learn (and generally agree) that post-translational control is important, but measuring this has been much trickier than assessing gene expression or protein abundance, which have over time become a surrogate for 'activity'. A lab at the University of Dundee have designed an ingenious way to specifically measure the activity (rather than the abundance) of a particular class of enzyme that has profound importance in all aspects of cell biology - the 'E3 ubiquitin ligase' (E3). E3s act like 'sticker-guns', labelling other proteins with a small protein modification called ubiquitin. Ubiquitin-labelled proteins are most commonly sent to the cell's molecular waste disposal system for recycling. Some E3s are known to help viral infections progress (pro-viral) while others hinder the progression of infection (antiviral). Manipulating these activities could lead to new innovative therapies to control viral infections. The technology - called an 'Activity-based probe' (ABP) - works by mimicking the E3s main partner in life, the E2 ubiquitin conjugating (E2) enzyme. E2s bind transiently to active E3s in cells; an E2-based ABP binds irreversibly to E3s, trapping it and divulging its prior state of activation. So, using the ABP allows me to sort the 'wheat from the chaff' and discover which E3s we should be focusing on when we talk about 'host-directed therapy'. Three particularly pernicious infections which show few signs of abating are human immunodeficiency virus (HIV) and influenza A virus (IAV). HIV is a pandemic infection; IAV has the potential for pandemics. Using these two virus infections models, I will look for common and divergent 'molecular signatures' in the host's E3 activity response that might signpost the way to novel therapies. I will infect cells with a virus, and then send the ABP scouts inside the infected cell, where they reveal a panorama of E3 activity change during the course of infection. Identifying convergent molecular signatures in our cells might even signpost the way to broad-spectrum host-directed therapies.