Download Target Discovery Approach (English)

A brief overview of Galapagos
Galapagos is a drug discovery company focused on finding new drugs against
diseases that affect the joints and bones. This summary gives a brief introduction to
Galapagos’ technology and explains how its unique approach could help bring new
drugs to the market.
The human genome, or blueprint for all of the cells in the human body, is made up
of tens of thousands of genes. Genes are composed of DNA and contain the
instructions for building all of the cell’s proteins. Proteins control the structure and
function of all of the cells that make up the human body. Before a cell can use the
DNA to make protein, the DNA must first be re-written into RNA. The cell’s
machinery then uses the RNA to produce protein. Therefore, the process of making
protein in the cell goes from DNA to RNA to protein (see the yellow box in Figure 1).
Nearly all diseases and disorders are caused by a disruption in the normal function of
certain proteins. Therefore, the main goal of pharmaceutical companies is to design
drugs that alter the activity of these proteins so that normal function returns and the
cause of the disease is minimized or eliminated. One of the main obstacles in
discovering new drugs is knowing exactly which of the body’s thousands of proteins
play a key role in a particular disease. Once these proteins are discovered, they
become targets for drug design. Finding these targets is one of the critical steps in
the drug discovery process.
In order to study proteins in human cells, Galapagos takes advantage of the
distinctive properties of adenoviruses. Adenovirus is the virus that causes the
common cold and has the capability to infect almost every type of human cell, which
is the reason it is so contagious. The adenoviruses Galapagos works with have been
engineered to act as a shuttle vehicle, allowing the delivery of specific pieces of DNA
into human cells. Additionally, these viruses have been made replication
incompetent, meaning they are unable to reproduce outside of the laboratory
environment, and are therefore a safe vehicle for the delivery of DNA into human
cells. Figure 1 shows how the viruses deliver these pieces of DNA into human cells in
the laboratory, causing the cells to either make more of a certain protein (knock-in)
or to block the production of new protein (knock-down).
KnockKnock-down
KnockKnock-in
SilenceSelect ®
FLeXSelect ®
Knock-down vs knock-in
DNA
DNA
DNA
RNA
RNA
RNA
protein
protein
protein
amount of protein
after knockknock -in
amount of protein
in normal cells
amount of protein
after knockknock -down
Figure 1: Comparison of a specific protein’s amount
before and after knock-in or knock-down.
Knock-down viruses work by making
small pieces of RNA (siRNA), which
bind to a specific RNA sequence that
produces a particular protein. After
the siRNA binds the RNA, the RNA is
cut by the cell’s machinery, therefore
stopping the RNA from making
anymore of the protein. This process
is called RNA interference (RNAi)
and results in a reduction in the
amount of the specified protein.
For the knock-in viruses, a specific
piece of DNA (which contains the
instructions to produce a specific
protein) is inserted into the virus.
After the virus infects the cell, the
cell starts to produces more of the
corresponding protein.
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Galapagos combines the ability to alter the amount of protein in human cells with a
high-throughput screening method. Using this method, Galapagos is able to
run many small-scale experiments simultaneously. Operating on a grid system,
where each square corresponds to a small test tube with cells that have undergone a
change in a specific protein, Galapagos can screen many thousands of proteins in a
short period of time.
Viruses containing specific pieces of DNA are
arranged on a grid.
Each virus delivers this specific piece of DNA
into the cells, causing a particular protein to be
k nock eded-in or k nock eded-down. Therefore, each
square on the grid contains cells that have
undergone a change in the amount of
a specific protein.
Experiments are designed to monitor (by, for
example, a color change) the effect the protein
change has on the cells. Because this change
corresponds to a specific protein, the protein
can be further investigated and eventually
become a drug target.
Figure 2: High-throughput screening technique: using adenoviral collections to screen human cells.
Based on their function and design, proteins are divided into several classes.
Researchers in the pharmaceutical industry generally agree that certain classes of
proteins respond to drugs better than other classes. These classes of proteins are
referred to as drugable and form the basis of most drug research programs.
Galapagos has constructed a focused collection of viruses that either knock-in
(FLeXSelect®) or knock-down (SilenceSelect®) the drugable proteins. With these
collections, Galapagos has screened human cells that are affected by diseases like
osteoarthritis, osteoporosis and rheumatoid arthritis, and has identified proteins that
control the disease. By further testing (validating) these proteins in more advanced
studies, Galapagos has found a number of targets suitable for new drug
development.
Galapagos is currently conducting drug discovery research based on the targets
discovered using this technology. Once a target is validated, it is tested against large
collections of chemical small molecules to identify the structures that interact (block
or activate) with the target. These chemical structures are then optimized to obtain
“drug-like” characteristics followed by testing of the drug candidate in the clinic. This
process of drug discovery is similar to the approach taken by large pharmaceutical
companies and has resulted in breakthrough medicines such as Gleevec®, a recently
approved oncology product by Novartis.
Galapagos’ uniqueness lies in using human cells, which gives a more realistic idea of
the effect that protein might have on the disease in the human body than studying
proteins in engineered cells (cell lines) and animal cells, as other companies do.
Moreover, Galapagos concentrates its efforts on the drugable proteins and can
efficiently screen these proteins in human cells. Galapagos believes that this unique
approach to target identification and validation increases the chances of success in
bringing new drugs to the market.
In addition to forming the basis of Galapagos’ internal target discovery activities,
these adenoviral collections and screening technologies are also available to
academic institutes and pharmaceutical companies through BioFocus, a Galapagos
services unit. Numerous partners have already applied Galapagos’ technology across
a number of disease areas, aiding the scientific and pharmaceutical communities to
better understand the cause of disease and further progressing the development of
new drugs.