Writing today (Oct. 28, 2013) in the journal Virology, a team led by UW-Madison biochemistry Professor Ann Palmenberg provides a meticulous topographical model of the capsid or protein shell of a cold virus that until 2006 was unknown to science.
Two faces of the common cold. The protein coat of the “missing link” cold virus, Rhinovirus C (right), has significant differences from the more observable and better studied Rhinovirus A. Those surface differences, revealed in a new three-dimensional model of Rhinovirus C from the UW–Madison lab of Ann C. Palmenberg, explain why no effective drugs have yet been devised to thwart the common cold.
Rhinovirus C is believed to be responsible for up to half of all childhood colds, and is a serious complicating factor for respiratory conditions such as asthma. Together with rhinoviruses A and B, the recently discovered virus is responsible for millions of illnesses yearly at an estimated annual cost of more than $40 billion in the United States alone.
The work is important because it sculpts a highly detailed structural model of the virus, showing that the protein shell of the virus is distinct from those of other strains of cold viruses.
“The question we sought to answer was how is it different and what can we do about it? We found it is indeed quite different,” says Palmenberg, noting that the new structure “explains most of the previous failures of drug trials against rhinovirus.”
The A and B families of cold virus, including their three-dimensional structures, have long been known to science as they can easily be grown and studied in the lab. Rhinovirus C, on the other hand, resists culturing and escaped notice entirely until 2006 when “gene chips” and advanced gene sequencing revealed the virus had long been lurking in human cells alongside the more observable A and B virus strains.
The new cold virus model was built “in silico,” drawing on advanced bioinformatics and the genetic sequences of 500 rhinovirus C genomes, which provided the three-dimensional coordinates of the viral capsid.
“It’s a very high-resolution model,” notes Palmenberg, whose group along with a team from the University of Maryland was the first to map the genomes for all known common cold virus strains in 2009. “We can see that it fits the data.”
With a structure in hand, the likelihood that drugs can be designed to effectively thwart colds may be in the offing. Drugs that work well against the A and B strains of cold virus have been developed and advanced to clinical trials. However, their efficacy was blunted because they were built to take advantage of the surface features of the better known strains, whose structures were resolved years ago through X-ray crystallography, a well-established technique for obtaining the structures of critical molecules.
Because all three cold virus strains all contribute to the common cold, drug candidates failed as the surface features that permit rhinovirus C to dock with host cells and evade the immune system were unknown and different from those of rhinovirus A and B.
Based on the new structure, “we predict you’ll have to make a C-specific drug,” explains Holly A. Basta, the lead author of the study and a graduate student working with Palmenberg in the UW-Madison Institute for Molecular Virology. “All the [existing] drugs we tested did not work.”
Antiviral drugs work by attaching to and modifying surface features of the virus. To be effective, a drug, like the right piece of a jigsaw puzzle, must fit and lock into the virus. The lack of a three-dimensional structure for rhinovirus C meant that the pharmaceutical companies designing cold-thwarting drugs were flying blind.
“It has a different receptor and a different receptor-binding platform,” Palmenberg explains. “Because it’s different, we have to go after it in a different way.”
In addition to Basta and Palmenberg, co-authors of the new studies include Jean-Yves Sgro, Shamaila Ashraf, Yury Bochkov and James E. Gern, all of UW-Madison.
—Terry Devitt, 608-262-8282, email@example.com
The new rhinovirus C studies were supported by the National Institutes of Health, grants AI17331 and U19 AI104317.
Terry Devitt | Newswise
The genes are not to blame
20.07.2018 | Technische Universität München
Targeting headaches and tumors with nano-submarines
20.07.2018 | Universitätsmedizin der Johannes Gutenberg-Universität Mainz
A new manufacturing technique uses a process similar to newspaper printing to form smoother and more flexible metals for making ultrafast electronic devices.
The low-cost process, developed by Purdue University researchers, combines tools already used in industry for manufacturing metals on a large scale, but uses...
For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.
To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...
For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.
Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...
Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.
A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...
Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.
"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....
13.07.2018 | Event News
12.07.2018 | Event News
03.07.2018 | Event News
20.07.2018 | Power and Electrical Engineering
20.07.2018 | Information Technology
20.07.2018 | Materials Sciences