Virus Wars: Are E3-Targeted Therapies A New Hope?

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.

Who will benefit from this research and how?
Direct

1) Academia - This research makes use of a novel technology to address a major gap in our understanding of how our cells respond to viral infection - known as our 'innate immune system'. New information will be of interest beyond the sphere of virology and immunity however, because this same system is heavily involved in the cells response to DNA damage (e.g. radiation damage, ageing), neurotoxic aggregates (e.g. Alzheimer's Disease, Motor Neurone Disease) and even in how cells become cancerous, as many of the signalling pathways are shared. The primary route to academic impact will be active dissemination of my results via publications and by giving talks. By the end of Year 4, I will create an open, feely accessible and interactive online tool for the community to search our data.

2) Private Sector - 'Proteolysis targeted chimeras' (PROTACs) are small drugs that recruit an E3 enzyme to a target of interest and sentencing it to destruction. The private sector is heavily invested in PROTACs but is hindered by lack of understanding of which E3 enzyme can be commandeered. My research will signpost the active E3s during infection and therefore suggest which are the most tractable targets. I will engage with the private sector via the University of Glasgow Knowledge Exchange and Innovation Strategy. Commercialisation or creation of IP has the potential to contribute to the UK's wealth.

Indirect

1) Policy makers - Local policymakers will be the CVR and University of Glasgow. My research will affect their strategic goals and funding strategies. This research could have impact on healthcare by speaking with NHS via local board and national levels, delivering a strong message on how viral infections cause effects on our immune systems. This level of engagement can occur from the start of the fellowship.

2) Public sector - Charities funding related research (like the Wellcome Trust) may be interested to fund projects that arise as a result of this research.

3) The wider public - By becoming a STEM ambassador and performing science outreach, I will inform the public of our work and its implications.