An unusual RNA structure in the SARS virus offers a promising target for antiviral drugs

Even if SARS is a distant memory (from last year), research is still ongoing to understand this deadly virus. Californian researchers determined by X-Ray spectroscopy the 3D structure of the RNA genome of SARS. They found unusual and very interesting features, including a rare 90 degree bend. The unique structure could be a promising target for future drug development against SARS.

The article can be downloaded for free at the PLoS journal website.

The press release from the University of California (Santa Cruz)
: Research on the genome of the virus that causes severe acute
respiratory syndrome (SARS) has revealed an unusual molecular structure
that looks like a promising target for antiviral drugs. A team of
scientists at UCSC has determined the three-dimensional shape of this
structure, an intricately twisted and folded segment of RNA. Their
findings suggest that it may help the virus hijack the protein-building
machinery of infected cells.
The SARS virus is a type of RNA virus, meaning that its genetic
material is RNA rather than the more familiar DNA found in the
chromosomes of everything from bacteria to humans. All RNA viruses have
relatively high mutation rates, making their genomes highly variable.
In HIV, for example, this high rate of mutation contributes to the
rapid appearance of drug-resistant strains of the virus. In SARS and
related viruses, however, one segment of the RNA genome--known as the
s2m RNA--remains virtually unchanged.
"Because viral evolution has not been able to tamper with this
sequence, it is clear that it must be of vital importance to the
viruses that have it, but no one knows exactly what its function is,"
said William Scott, an associate professor of chemistry and
biochemistry.
Scott's lab used the technique of x-ray crystallography to solve the
structure of this RNA element with nearly atomic resolution, revealing
where every one of the many thousands of atoms that make up the
structure is situated. The results showed several unique and
interesting features of the s2m RNA, including a distinctive fold that
appears to be capable of binding to certain proteins involved in
regulating protein synthesis in cells.
"The structure gives us strong hints about the function, because it
forms a fold that has been implicated in binding a certain class of
proteins," Scott said. "The structure itself also provides a starting
point for designing antiviral drugs that might bind to this RNA and
prevent it from doing whatever it is that is vital to the life cycle of
the virus."
The UCSC researchers are publishing their findings in the journal PLoS
Biology (http://www.plosbiology.org, Volume 3, Issue 1). The first
author of the paper is Michael Robertson, a postdoctoral researcher in
Scott's lab. Robertson and Scott purified large amounts of s2m RNA,
crystallized it, bombarded the crystals with x-rays, and determined the
structure from the resulting pattern of x-ray scattering.
The other coauthors, in addition to Scott, are Manuel Ares, professor
of molecular, cell, and developmental biology and a Howard Hughes
Medical Institute (HHMI) professor; Haller Igel, a research associate
in the Ares lab; David Haussler, professor of biomolecular engineering
and a HHMI investigator; and Robert Baertsch, a graduate student
working with Haussler.
All of the authors are affiliated with UCSC's Center for Molecular
Biology of RNA. The strong interdisciplinary connections within the RNA
center were a key to making the project possible, Scott said. The
investigation brought together bioinformatics experts Baertsch and
Haussler, who performed the computational sequence analysis of the
genomes of SARS and related viruses; molecular biologists Igel and
Ares, who cloned and chemically characterized the s2m RNA; and RNA
crystallography experts Robertson and Scott.
"It's true that exciting discoveries are often made at the interfaces
between disciplines, but it's rare that you see it happening in such a
vivid way. This is a great example of interdisciplinary science at
work," said Harry Noller, Sinsheimer Professor of Molecular Biology at
UCSC and director of the RNA center.
Different types of RNA perform a variety of critical tasks in all
living cells. Messenger RNA is the intermediary that carries genetic
information from the DNA in the chromosomes to the cellular protein
factories, called ribosomes, where the genetic information is
translated into proteins. The ribosomes themselves are made primarily
of ribosomal RNA.
The SARS s2m RNA is in an untranslated section at one end of each of
the messenger RNAs that direct the production of viral proteins in
infected cells.
"It hangs on the tail end of the messenger RNA like a little molecular
knob," Noller said.
Noller, an expert on the ribosome, noticed that a sharp, 90-degree bend
in the s2m RNA structure is similar to a part of the ribosome. "It may
only be a superficial resemblance, but you don't often see this kind of
right-angle bend in RNA," Noller said.
This part of the ribosome and the proteins that bind to it are involved
in the regulation of protein synthesis, leading Scott and his coauthors
to hypothesize that the s2m RNA, by mimicking the ribosomal binding
site, may serve to hijack the host cell's protein-synthesis machinery
for use by the virus. This hypothesis will have to be tested by further
studies, which are already under way in Ares's lab.
"The precise function is something they're going to figure out, no
doubt about it, and it's bound to be something of major importance,"
Noller said. "When you see a whole class of viruses that have this
absolutely conserved structural element, it tells you there's something
really interesting going on here."
Sequence analysis by Haussler and Baertsch found that viruses in two
families--coronaviruses (which include the SARS virus) and
astroviruses--share the s2m element. About 75 percent of this sequence
is absolutely invariant between viral species. Furthermore, an analysis
of 38 different SARS variants found absolutely no variation within the
s2m sequence.
Other scientists had previously noticed this highly conserved element
in astroviruses and a few other viruses, and had given it the s2m name.
But no one had any idea what the s2m RNA does that would explain why it
is so highly conserved, Haussler said.
According to Scott, the UCSC team's investigation represents a novel
approach in the field known as structural genomics. A more common
approach in structural genomics is to determine the three-dimensional
shape of a novel protein and compare it to the shapes of proteins with
known functions to find clues to the function of the unknown protein.
"We have taken the methodology of conventional structural genomics and
extended it to investigate the structure of the RNA genome itself,"
Scott said.
Ultimately, this research could lead to the development of antiviral
drugs that would bind to the s2m RNA and prevent it from carrying out
its function. Such drugs might be effective against a range of
coronaviruses and astroviruses. While the SARS virus is the most deadly
of these, other coronaviruses are common causes of respiratory
infections in humans and other animals. Although none of the other
human coronaviruses have the s2m RNA, several important animal
pathogens do and would be susceptible to a drug that targets s2m.
Astroviruses, meanwhile, are a leading cause of gastrointestinal
infections, second only to rotaviruses as a cause of childhood
diarrhea. In developing countries, diarrhea is a major cause of death
in children. A drug that blocks s2m could help alleviate this
suffering, as well as provide another tool in the fight against SARS.