New weapons
against emerging viruses
When a new virus appears on the scene, it takes a long time to develop the drugs
needed to stop it in its tracks. Now the VIZIER (‘Comparative structural genomics of
viral enzymes involved in replication’) project is ensuring that in the future, scientists
will be able to react rapidly and develop new drugs against a major class of viruses
within weeks.
The project has already made important breakthroughs. New viruses
carried by ticks and rodents have been identified, and findings made
within VIZIER have been taken up by pharmaceutical companies
developing drugs to treat Dengue Fever and Respiratory Syncitial
Virus.
VIZIER is the world’s largest structural genomics project to date, bringing
together 23 partners from 9 EU Member States, plus Russia. The
team brings together scientists from virology, protein work, biochemistry,
crystallography and drug design, among other fields.
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Waking up to the threat
The relative absence of deadly viruses in Europe has lulled many
of us into a false sense of security about the threats to our health.
But when the world was hit by Avian Influenza and Severe Acute
Respiratory Syndrome (SARS) outbreaks in recent years, it became
more apparent than ever that Europe is not immune to the threats
of new and lethal viruses. Meanwhile, known viruses continue to
claim the lives of millions of people in less developed parts of the
world.
The VIZIER project is focusing its efforts on RNA viruses, so named
because of the ribonucleic acid in their genetic material. Over 350 RNA
viruses which can infect humans have been identified, including gastroenteritis,
measles, influenza, yellow fever and hepatitis C. Together
they are the cause of millions of deaths every year, yet our knowledge
of their genetic make up and structures is relatively poor.
The aim of VIZIER is to investigate over 300 of these viruses in depth
with the aim of identifying new drug targets. The team’s research
takes place in five stages: collecting viruses, sequencing them, protein
production, crystallisation and the initial steps of drug discovery
and design.
A step-by-step approach to understanding viruses
The research begins with the collection of viruses from around the
world. When the project began, many of these viruses were already
stored in some of the project partners’ laboratories. But others had
to be collected. In doing so, the project has created a series of biodiverse
libraries that should help scientists to deal with any future virus
outbreaks.
Once they have been collected, the genome of the virus is sequenced.
Sequencing allows scientists to see what is involved in the replication
of each individual virus and also create a three-dimensional
model of the protein produced by the virus.
Using bacteria to farm proteins
The next stage of the project involves investigating the proteins
involved in virus replication. The gene for the protein is injected into
a bacterium, which is used as a factory to create the protein. While
this works for some proteins, others have to be grown in a cell closer
to that in which it would normally live. High-tech labs in France and
the UK are being used for this part of VIZIER.
The next stage – crystallisation – is where VIZIER has had many of its
breakthroughs. Indeed, the success of the project depended upon
crystallisation of proteins, as crystals are essential for determining the
molecular form of the protein that spreads a virus and thus for developing
drugs. Results here have exceeded expectations, according to
project coordinator Bruno Canard from the Université de la
Méditerranée in France. Over 70 new crystal structures of original
viruses within the RNA virus family have already been created.
VIZIER clears obstacles to crystal creation
Previous projects have had only limited success with creating crystals.
Dr Canard believes that VIZIER succeeded where others experienced
difficulties because of the multidisciplinary nature of the project and
the exceptional communication between the partners.
The high-throughput methods used by the project also proved to be
groundbreaking. Creating crystals is often the bottleneck of this type
of research. The previously laborious process involved one scientist
working solely on one protein. Discoveries could take years. VIZIER’s
high-throughput methods, involving robotics, are what made the
creation of so many crystals possible.
Once the crystals are formed, they are put into a synchrotron. The
ring of the synchrotron carries electrons travelling close to the speed
of light. They produce an intense source of X-rays that can be used to
illuminate the molecular form of the proteins within. Knowledge of
this molecular form can help scientists to design a compound that
will stop the virus from replicating.
Preparing for future epidemics
Knowing that one virus is similar in structure to another provides clues
as to which compounds might work. When SARS emerged in 2002,
previous work on related viruses meant that a potential drug was
developed within weeks of the virus being identified. The epidemic
claimed 774 lives, but this number could have been devastatingly
higher. The VIZIER project was set up in the aftermath of this crisis,
with the aim of ensuring that reaction times will be equally fast if and
when a new virus emerges. All findings will be stored in databases
that can be accessed by the scientific community.
We don’t know where the next deadly virus will come from, or when
it will strike, but thanks to projects like VIZIER, we will be better
equipped to respond to it before it turns into a full-blown epidemic.