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, Yorkshire Kidney Research Fund (Jul 2016), £108,285
Amanda Bretman, Leverhulme Trust
(Jul 2016), £107,128
Zarah Timsah, Wellcome Trust
(Jul 2016), £100,000
Adrian Whitehouse, Worldwide Cancer Research (Jul 2016), £107,570
Roman Tuma, BBSRC (Jul 2016), £107,433
Helen Miller, Innovate UK (Jun 2016), £109,647
Adrian Goldman, Royal Society
(Jun 2016), £250,000
James Deuchars, Dunhill Medical Trust (Jun 2016), £107,247
Keith Hamer, DEFRA Dept for Env. Food & Rural Affairs
(Jun 2016), £103,887
Richard Bayliss, EU - European Union
(Jun 2016), £108,176
Jamel Mankouri, British Lung Foundation
(Jun 2016), £105,557
Jamel Mankouri, John Barr, British Lung Foundation
(Jun 2016), £24,000
Zahra Timsah, Wellcome Trust (Jun 2016), £108,605
Andrew Macdonald, Kidney Research Fund UK
(Jun 2016), £108,110
Andrew MacDonald, Richard Foster, Stephen Griffin, Kidney Research Fund UK
(Jun 2016), £63,653
Edwin Chen, Academy of Medical Sciences (Jun 2016), £108,131
Edwin Chen, Academy of Medical Sciences
(Jun 2016), £98,110
Adrian Goldman, Royal Society (May 2016), £106,738
Peter Stockley, Wellcome Trust (May 2016), £1,246,487
John Ladbury, Christopher Jones, Cancer Research UK
(May 2016), £6,905
Elton Zaqiraj, Wellcome Trust (May 2016), £1,093,823
Adrian Whitehouse, Julie Aspden, BBSRC (May 2016), £457,270
Alison Baker, Miller Camargo-Valero, BBSRC
(May 2016), £451,124
Peter Urwin, BBSRC (May 2016), £432,379
John Trinick, R Elwyn Issac, Leverhulme Trust
(May 2016), £171,742
, British Council, UK
(May 2016), £17,793
Mark Harris, Horserace Betting Levy Board
(Apr 2016), £10,000
Peter Stockley, Neil Ranson, Roman Tuma, David Rowlands, MRC (Apr 2016), £341,225
Jamel Mankouri, Royal Society (Apr 2016), £332,396
Andrew Tuplin, MRC (Apr 2016), £508,170
Keith Hamer, DEFRA Darwin Initiative (Apr 2016), £327,744
Simon Goodman, British Council, UK
(Mar 2016), £35,800
, British Council, UK
(Mar 2016), £12,802
Katie Field, NERC
(Mar 2016), £186,411
Isuru Jayasinghe, Royal Society
(Mar 2016), £14,919
William Hoppitt, EU (Feb 2016), £34,345
Helen Miller, ABNA Ltd (Feb 2016), £115,000
Sarah Calaghan, Isuru Jayasinghe, BHF (Jan 2016), £52,050
Edwin Chen, Wellcome Trust (Jan 2016), £98,341
Patricija Van Oosten-Hawle, Wellcome Trust (Jan 2016), £89,900
James Duce, Alzheimer's Society (Jan 2016), £84,834
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
Thomas Edwards and colleagues in the School of Chemistry, EPSRC (Jan 2016), £2,228,732
David Brockwell, Sheena Radford, BBSRC (Dec 2015), £358,570
Stephanie Wright, Kay Kendall Leukaemia Fund (Dec 2015), £207,286
Stefan Kepinski, Michelle Peckham, BBSRC (Nov 2015), £461,760
Ryan Seipke, BBSRC (Nov 2015), £340,536
Paul Knox, BBSRC (Nov 2015), £40,000
Helen Miller, Agriculture & Horticulture Develpmnt Brd (Oct 2015), £63,560
Jessica Kwok, Wings For Life Spinal Cord Research (Oct 2015), £134,981
Joe Cockburn, Royal Society (Oct 2015), £14,960
Alison Ashcroft, Peter Stockley, Sheena Radford, Nicola Stonehouse, David Brockwell, Darren Tomlinson, BBSRC (Oct 2015), £340,937
Alan Berry, Wellcome Trust (Oct 2015), £752,365
Mark Harris, Thomas Edwards, John Barr and colleagues from the School of Chemistry, Wellcome Trust (Sep 2015), £204,959
Mark Harris, Royal Society (Sep 2015), £74,000
Zahra Timsah, Royal Society (Sep 2015), £15,000
Katie Field, Royal Society (Sep 2015), £14,700
Christine Foyer, Royal Society (Sep 2015), £12,000
Julie Aspden, MRC (Sep 2015), £633,020
Ian Hope, Marie-Anne Shaw, BBSRC (Aug 2015), £381,998
Helen Miller, ABNA Ltd (Aug 2015), £22,968
Alan Berry, Alex Breeze, Adam Nelson, BBSRC (Aug 2015), £479,490
Katie Field, BBSRC (Aug 2015), £830,381
Tim Benton, M & W MACK LTD (Aug 2015), £48,711
Neil Ranson, Mark Harris, Ade Whitehouse, Peter Stockley, Sheena Radford, Alan Berry, Wellcome Trust (Jul 2015), £1,000,000