Outsmart Ebola Together – a collaboration project using idle computers to search for compounds to cure Ebola
The World
Community Grid, a volunteer computing platform developed by IBM that uses the idle
computer time of internet-connected computers to perform research calculations,
has teamed up with the Scripps Research Institute to help find chemical
compounds to fight Ebola Virus Disease.
The aim of
this collaboration project called ‘Outsmart
Ebola Together’ is to find drugs with high binding affinity with certain of
the Ebola virus’ proteins, which can then block the crucial steps in the life
cycle of the virus. Currently two targets have been identified: a surface
protein used by the virus to infect human cells, and "transformer"
proteins which change shape to carry out different functions.
Deadly pathogen
The Ebola virus is a
member of the filovirus or Filoviridae
family and is shaped like a long, flexible filament. This filament can attach
itself to cells and penetrate the cells. The virus then uses the host cell’s
mechanisms to replicate itself after which numerous copies of the virus are
then released to further infect nearby cells. The result of this repeat
infection and replication results in clotting of the blood, leakage from blood vessels,
inflammation, organ failure and shock. Infection only occurs by contact with an
infected person’s bodily fluids or the body of patient who died from the disease.
The virus cannot be transmitted through the air or water. Other members of the
filovirus family are Marburg, Sudan and Reston viruses, which are all very
virulent and deadly pathogens. These four viruses all have caused outbreaks in 2014
in Africa and Asia (animals only). The Ebola virus has infected over 15,000
people and killed at least 7,500 in West Africa (data of WHO),
representing a case-fatality rate of 36%.
Therapeutic agents under consideration
Currently there are no
treatments or vaccines available, but numerous research projects are ongoing,
esp. since the 2014 outbreak. This has been confirmed by Marco
Cavalari, head of Anti-infectives and Vaccines at the European Medicines
Agency (EMA). The EMA
has reviewed several potential treatments for Ebola in order to have an
overview of data from these treatment and to support decisions on potential
emergency use for individual patients. However, they found that evidence for
safety and efficacy of the included treatments (which were selected as they
have direct virus activity) was not yet sufficient to draw any conclusions. The therapeutic agents considered by the EMA
were three nucleos(t)ide polymerase inhibitors (BCX4430, Brincidofovir and
Favipiravir), two oligonucleotide based products (TKM-100802 and AVI-7537), a
cocktail of monoclonal antibodies (ZMapp) and polyclonal immunoglobelins
derived from immunized horses (Anti-Ebola F(ab’)2 fragments). These potential
treatments are all based on newly developed compounds or compounds currently
registered for treatment of other viruses. The WHO has confirmed that two vaccines are in safety
trials for use in Ebola affected countries.
Millions of candidate drug molecules
The Outsmart Ebola
Together project of the World Community Grid and the Scripps Research Institute
however uses a different approach as it is screening the structures of millions
of known candidate drug molecules (ligands) against the atomic structure of the
target Ebola virus molecule (targets). This screening by using computers,
called in-silico screening, uses
specific software developed by the Olson Laboratory at the Scripps Research
Institute. The target and ligand are evaluated with regard to binding affinity
between the molecules. Such screening is traditionally done in a laboratory
using test tubes and actual chemicals which have to synthesized first is
sufficient quantity, a very laborious and costly business. The screening can
however also be done by using software in which the structures of the target
and ligands are analyzed and will result in the binding affinity value. The Scripps
Research Institute has already solved the structures of the critical target proteins of the virus and
converted these to molecular images. Two of these targets have been identified
for inclusion in the Outsmart Ebola Together collaboration project.
Transformer protein
The first target is a
surface protein on the Ebola virus that is responsible for injection of new
human cells. This target protein is similar for Ebola, Marburg, Reston and
Sudan viruses so it could potentially lead to a drug effective against any of
these viruses. The second target is a so called shape-shifting ‘transformer’
protein of the Ebola virus, which adopts different forms at different times of
the virus lifecycle to achieve different functions.
If a suitable
candidate drug molecule, based on a high binding affinity with the Ebola virus
protein, has been selected, this can then be tested in the lab. Additional
trials will then be necessary to optimize the compound and find a suitable
formulation of a drug product. All results from the Outsmart Ebola Together
project are shared so that other scientists around the world can use this data
as well in their own research to find a cure Ebola. The Scripps Research
Institute in La Jolla, California, USA is a non-profit research institution which
is on the forefront of such ‘open source’ research in the biosciences.
On 30 December, the
project had already ‘run’ for 132 years, 155 days and 16 hrs, generating
193,870,193 points and returned 491,434 results. This is only 1% of the
project. You can help the researchers by donating your computing power to this
project. Anyone with a computer, smartphone or tablet can donate their unused
computing powder to scientists by installing an application on these devices which
runs when they are not using the full capacity of their computer. By connecting
all these computers, the World Community Grid is essentially a virtual
supercomputer, using its computational power for humanitarian research. Other
projects include the Clean Energy Project and the FightAIDS@home project.
