"Plugging the holes in COVID-19 therapy"

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV2), has claimed over 1.4 million lives, infected almost 60 million people and caused profound morbidity and socioeconomic damage worldwide. Clinical management of severe disease has improved and recent vaccine trials are highly encouraging. However, a significant number of people may be unable to either receive or respond to a vaccine due to underlying immunological issues. Unfortunately, trials repurposing existing drugs as SARS-CoV2 antivirals have yet to yield convincing therapies. One overlooked, but essential drug target in SARS-CoV2 is the envelope (E) protein, which forms a virus-encoded ion channel, or "viroporin" that plays an essential role during the formation of infectious virus particles and also how they infect naïve cells. In addition, E is thought to interfere with host inflammatory responses. Thus, drugs capable of blocking E function could combat COVID-19 on two distinct fronts. We have worked on viroporins from several clinically important viruses, including hepatitis C virus, pandemic influenza and Zika virus, for many years. We use and generate structural information about channel complexes to help design and select small molecules as potential antivirals, but which also serve as tools to understand the fundamental biology of these proteins. Now, turning to SARS-CoV2 E, we have already identified existing drugs that potently block its activity, and we hope to rapidly advance these as new therapies. However, existing structures for E channels aren't consistent with drug binding, likely due to their being only partial domains or solved in unnatural environments. The aims of this PhD project, therefore, are: 1. To solve the full atomic structure of SARS-CoV2 E channels in membranes using cryo-EM 2. To use this structure to develop potent new antivirals targeting E channel activity 3. To exploit new drugs to understand how E influences SARS-CoV2 during infection The student on this project will have a unique opportunity to integrate molecular virology, structural biology and medicinal chemistry to address the most profound challenge to human health in over a century. Training and using state-of-the-art facilities such as the Titan Krios electron microscopes, high-powered computing, advanced bio-imaging and Biological Safety Level (BSL) 3 containment laboratories will ensure all aspects of the project are able to thrive and generate meaningful, publication quality results. The student will gain both interdisciplinary and quantitative skills, taking an increasingly leading role as the project continues and develops.