The team are the first to observe at a single-molecule level how the genetic material (genome) that forms the core of a single-strand RNA virus particle packs itself into its outer shell of proteins. Lead researcher Professor Peter Stockley said their results overturn accepted thinking about the process and could open a chink in the armour of a wide range of viruses.
"If we can target this process, it could lead to a completely new class of anti-virals that would be less likely to create resistant viruses than existing drugs, which tend to target individual proteins," Professor Stockley said.
A number of important viruses like the common cold and polio have RNA (ribonucleic acid) instead of DNA as their genetic material. The observations reveal that the viruses' RNA initially has a much greater volume than the virus particles created after they are packed inside their protein shell.
"We realised that the RNA genome must have to be intricately folded to fit into the final container, just like when you pack to go on holiday and need to fold your clothes to fit into the space in your suitcase," said co-author Dr Roman Tuma from the University of Leeds' Faculty of Biological Sciences.
When the team added proteins to the viral RNA they saw an immediate collapse in its volume.
"It seems that viral RNAs have evolved a self-folding mechanism that makes closing the 'viral suitcase' very efficient. It's as though 'the suitcase and the clothes' work together to close the lid and protect the content," Dr Tuma said.
"The viral RNAs, and only the viral RNAs, can do this trick of folding up to fit as soon as they see the 'suitcase' coming. That's the important thing. If we can interfere in that process we've got a completely novel drug target in the lifecycle of viruses," Professor Stockley said.
"At the moment there are relatively few antiviral drugs and they tend to target enzymes that the virus encodes in its genome. The problem is that the drugs target one enzyme initially and, within the year, scientists are identifying strains that have become resistant. Individual proteins are extremely susceptible to this mutation. A fundamental process like the one we're looking at opens the possibility of targeting the collective behaviour of essential molecules, which could be much less susceptible to developing resistance," explained Professor Stockley.
The same phenomenon is seen in both bacterial and plant viruses. "While we have not proved it yet, I would put money on animal viruses showing the same mechanism too," Professor Stockley added.
The team used sophisticated instrumentation custom built at the University that allowed them to make the first ever single-molecule measurements of viral assembly. This allowed researchers to observe individual viral particles one at a time. "The specific collapse, which can only be seen in such assays, was totally unexpected and overturns the current thinking about assembly," Professor Stockley said.
The team also includes PhD student Alexander Borodavka, whose Wellcome Trust studentship funded the new research. They have recently secured a grant from the Biotechnology and Biological Sciences Research Council (BBSRC) to extend their research.
"We're now perfectly positioned to pursue questions about how this mechanism works in other viruses and we're already thinking about ways to start designing new antiviral drugs that would target this newly recognised feature of viral lifecycles," Professor Stockley said.
The research is published in the Proceedings of the National Academy of Sciences (PNAS).
Andrew MacDonald, Richard Foster, Stephen Griffin, Kidney Research Fund UK
(Nov 2016), £63,653
Elton Zaqiraj, Wellcome Trust (Aug 2016), £1,093,823
Peter Stockley, Wellcome Trust (Jul 2016), £1,246,487
Alison Baker, Miller Camargo-Valero, BBSRC
(Jul 2016), £451,124
Edwin Chen, Wellcome Trust (Jul 2016), £98,341
Edwin Chen, Academy of Medical Sciences
(Jul 2016), £98,110
Adrian Goldman, Royal Society
(Jun 2016), £250,000
Zarah Timsah, Wellcome Trust
(Jun 2016), £100,000
John Ladbury, Christopher Jones, Cancer Research UK
(May 2016), £6,905
Adrian Whitehouse, Julie Aspden, BBSRC (May 2016), £457,270
Jamel Mankouri, Royal Society (May 2016), £332,396
John Trinick, R Elwyn Issac, Leverhulme Trust
(May 2016), £171,742
Jamel Mankouri, John Barr, British Lung Foundation
(May 2016), £24,000
Stefan Kepinski, Michelle Peckham, BBSRC (Apr 2016), £461,760
David Brockwell, Sheena Radford, BBSRC (Apr 2016), £358,570
Peter Stockley, Neil Ranson, Roman Tuma, David Rowlands, MRC (Apr 2016), £341,225
Ryan Seipke, BBSRC (Apr 2016), £340,536
Keith Hamer, DEFRA Darwin Initiative (Apr 2016), £327,744
Katie Field, NERC
(Apr 2016), £186,411
Simon Goodman, British Council, UK
(Apr 2016), £35,800
, British Council, UK
(Apr 2016), £17,793
, British Council, UK
(Apr 2016), £12,802
Mark Harris, Horserace Betting Levy Board
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Neil Ranson, Mark Harris, Ade Whitehouse, Peter Stockley, Sheena Radford, Alan Berry, Wellcome Trust (Mar 2016), £1,000,000
James Duce, Alzheimer's Society (Mar 2016), £84,834
Isuru Jayasinghe, Royal Society
(Mar 2016), £14,919
Peter Urwin, BBSRC
BBSRC (Feb 2016), £432,379
Thomas Edwards and colleagues in the School of Chemistry, EPSRC (Feb 2016), £2,228,732
Andrew Tuplin, MRC (Feb 2016), £508,170
Patricija Van Oosten-Hawle, Wellcome Trust (Feb 2016), £89,900
William Hoppitt, EU (Feb 2016), £34,345
Mark Harris, Thomas Edwards, John Barr and colleagues from the School of Chemistry, Wellcome Trust (Jan 2016), £204,959
Katie Field, BBSRC (Jan 2016), £830,381
Alan Berry, Alex Breeze, Adam Nelson, BBSRC (Jan 2016), £479,490
Sarah Calaghan, Isuru Jayasinghe, BHF (Jan 2016), £52,050
Paul Knox, BBSRC (Jan 2016), £40,000
Andrew Smith, Rosetrees Trust (Jan 2016), £20,000
Richard Bayliss, Cancer Research UK (Jan 2016), £10,000
Richard Bayliss, BBSRC (Jan 2016), £8,000
Richard Bayliss, MRC (Jan 2016), £8,000
Joe Cockburn, Royal Society (Dec 2015), £14,960
Katie Field, Royal Society (Dec 2015), £14,700
Stephanie Wright, Kay Kendall Leukaemia Fund (Dec 2015), £207,286
Zahra Timsah, Royal Society (Nov 2015), £15,000
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Alan Berry, Wellcome Trust (Oct 2015), £752,365
Julie Aspden, MRC (Oct 2015), £633,020
Steve Sait, NERC (Oct 2015), £386,061
Urwin, Howard Atkinson, BBSRC (Oct 2015), £200,293
Helen Miller, ABNA Ltd (Oct 2015), £115,000
Mark Harris, Royal Society (Oct 2015), £74,000
Eric Hewitt, Andrew Macdonald, Yorkshire Kidney Research Fund (Oct 2015), £46,621
Christine Foyer, Royal Society (Oct 2015), £12,000
Dave Westhead, Bloodwise (Sep 2015), £664,109
Ade Whitehouse, Alison Ashcroft, Ian Carr, BBSRC (Sep 2015), £438,975
Shaunna Burke, Andrea Utley, Sarah Astill, Arts Council of England (Sep 2015), £80,594
Samit Chakrabarty, Ronaldo Ichiyama, Intl Foundn for Research in Paraplegia (Aug 2015), £93,000
Helen Miller, Agriculture & Horticulture Develpmnt Brd (Aug 2015), £63,560
Tim Benton, M & W MACK LTD (Aug 2015), £48,711
Eileen Ingham, John Fisher, EPSRC (Jul 2015), £1,458,439
Anastasia Zhuravleva, BBSRC (Jul 2015), £483,019
Alex O'Neill, MRC (Jul 2015), £249,822
Ade Whitehouse, Richard Foster, Cancer Research UK (Jul 2015), £201,034
Ronaldo Ichiyama, Jim Deuchars, Sue Deuchars, Wings For Life Spinal Cord Research (Jul 2015), £123,895
Helen Miller, ABNA Ltd (Jul 2015), £22,968