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MRC DiMeN Doctoral Training Partnership: Plugging the holes in COVID-19 therapy


MRC DiMeN Doctoral Training Partnership

Leeds United Kingdom Computational Chemistry Microbiology Molecular Biology Pharmaceutical Chemistry Structural Biology Virology

About the Project

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:

To solve the full atomic structure of SARS-CoV2 E channels in membranes using cryo-EM

To use this structure to develop potent new antivirals targeting E channel activity

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.

The successful candidate will join a thriving virology community at Leeds, with a diverse portfolio of interests. The supervisors for this project interact regularly and have collaborated on multiple past projects. We are very happy to discuss the project and any other related aspects of our research or research groups. 

More information can be found here:

Griffin Lab, Ranson Lab, Foster Lab, as well as the Astbury Centre

Follow on Twitter: @SGriffin_Lab, @naranson

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards

Further information on the programme and how to apply can be found on our website:

https://bit.ly/3lQXR8A 


Funding Notes

Studentships are funded by the Medical Research Council (MRC) for 3.5yrs. Funding will cover UK tuition fees and stipend only. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme. Please read additional guidance here: View Website
Studentships commence: 1st October 2021
Good luck!

References

Shaw J, Gosein R, Kalita MM, Foster TL, Kankanala J, Mahato DR, Abas S, King BJ, Scott C, Brown E, Bentham MJ, Wetherill L, Bloy A, Samson A, Harris M, Mankouri J, Rowlands D, Macdonald A, Tarr AW, Fischer WB, Foster R, Griffin S. 2020. Rationally derived inhibitors of hepatitis C virus (HCV) p7 channel activity reveal prospect for bimodal antiviral therapy. eLife. 9:e52555
Scott C, Kankanala J, Foster TL, Goldhill DH, Bao P, Simmons K, Pingen M, Bentham M, Atkins E, Loundras E, Elderfield R, Claridge JK, Thompson J, Stilwell PR, Tathineni R, McKimmie CS, Targett-Adams P, Schnell JR, Cook GP, Evans S, Barclay WS, Foster R, Griffin S. 2020. Site-directed M2 proton channel inhibitors enable synergistic combination therapy for rimantadine-resistant pandemic influenza. PLOS Pathogens. 16(8): e1008716
Foster TL, Thompson GS, Kalverda AP, Kankanala J, Bentham M, Wetherill LF, Thompson J, Barker AM, Clarke D, Noerenberg M, Pearson AR, Rowlands DJ, Homans SW, Harris M, Foster R, Griffin S. 2014. Structure-guided design affirms inhibitors of hepatitis C virus p7 as a viable class of antivirals targeting virion release. Hepatology. 59(2), pp. 408-422

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