A new drug discovery system allows scientists to specifically
target members of an important family of enzymes, called
phosphatases, which were previously considered mostly
“undruggable”.
Scientists from the Medical Research Council (MRC) Laboratory of
Molecular Biology, in Cambridge, UK, demonstrated the
capabilities of the new system by identifying a molecule that
could successfully target a phosphatase to reduce the
accumulation of Huntington’s disease-associated proteins in the
brains of mice.
The findings, published in Cell, could enable scientists to
screen for drugs that can target specific phosphatases.
Phosphatases are a type of enzyme that are a key part of
signalling in cells – turning processes on and off. Most
signalling starts with an activation signal – often when a type
of enzyme called a kinase attaches a chemical tag, a phosphate
group, to specific proteins to change their function. The signal
is stopped by phosphatase enzymes, which cut off the phosphate
group.
There are more than 200 types of phosphatases involved in many
different processes in cells, so any drug must selectively target
only the right one, otherwise it will produce serious
side-effects or kill the cell.
Many drugs have been developed that can target specific kinases
(such as anti-cancer drugs), but developing drugs that can
specifically target particular phosphatases has proved difficult
– because the functional part that cuts off phosphate groups is
common to all phosphatases, so drugging one phosphatase inhibits
hundreds of them and kills cells.
Dr Anne Bertolotti from the MRC Laboratory of Molecular Biology,
who led the study, said: “For decades, with no way to selectively
target phosphatases, research into them has lagged behind kinases
and they’ve been described as undruggable. Our new system is only
a first step, but we hope cracking this problem will stimulate
phosphatase research and drug development.
“Targeting phosphatases – instead of kinases – is like targeting
the brake, rather than the accelerator, on signals in cells. By
inhibiting a phosphatase, we prolong a signalling event that has
already been turned on, which may offer safer ways to
specifically alter signalling in cells and help to create new
drugs with fewer side-effects.”
The new system builds on previous work by the same scientists in
which they created functional synthetic versions of phosphatase
proteins.
These synthetic phosphatases are tethered to chips so they can be
screened to find a molecule that binds to one type of
phosphatase, but to none of the other types. The successful
molecule is then tested in cells grown in a dish to check it is
safe before beginning testing in mice.
Targeting Huntington’s disease
The researchers used the system to discover a molecule that
showed promise in a mouse model of Huntington’s disease.
Many neurodegenerative diseases, such as Alzheimer’s, Parkinson’s
and Huntingdon’s diseases, feature misfolded proteins that
accumulate in cells in the brain. The researchers hoped that
slowing down a cell’s production of proteins could leave its
‘quality control machinery’ with more capacity to clear up the
misfolded proteins.
In this study, they aimed to slow down the cell’s protein
production machinery by targeting a specific phosphatase
(designated ‘PPP1R15B’). They used their new drug discovery
platform and found a molecule, called Raphin1, that targeted only
that phosphatase.
When they tested Raphin1 in a mouse model of Huntington’s
disease, they found it could cross into the brain where it
reduced the accumulation of the disease-associated misfolded
proteins in neurons. The scientists emphasise that this is early
stage research and more work is needed to test if the drug will
be safe or effective in humans.
Dr Anne Bertolotti said: “Since Huntington’s disease runs in
families and can be diagnosed genetically, early diagnosis could
provide what we hope is a window of opportunity to target the
disease before symptoms appear. Our unique approach manipulates
cells to slow down normal functions and give them a chance to
clear up the misfolded proteins that are characteristic of
Huntington’s. However, it will take some years before we know if
this approach works in humans and is safe.”
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Notes to editors
To speak to one of the authors, please contact the MRC Press
Office on 0207 395 2345 or email:
press.office@headoffice.mrc.ac.uk
‘Target-based discovery of an inhibitor of the regulatory
phosphatase PPP1R15B, by Krzyzosiak et al. is published today in
Cell. Link to the paper:
https://www.cell.com/cell/fulltext/S0092-8674(18)30798-0.
Images: two photos of neurons from mice treated with Raphin1
versus a placebo: one showing huntingtin protein (green)
accumulated in the cells of mice given a placebo; and the other
showing reduced build-up of huntingtin in cells from mice treated
with Raphin1.
Notes:
This study was funded by the MRC, the European Research Council,
the Human Frontier Science Program, EMBO and the Swiss National
Science Foundation.
The discovery platform works for serine/threonine phosphatases,
which make up the majority of phosphatases in human cells.
More information about the previous study on synthetic
phosphatases:
https://www2.mrc-lmb.cam.ac.uk/uncovering-action-selective-holophosphatase-inhibitor/
Paper in Nature Structural and Molecular Biology:
https://www.nature.com/articles/nsmb.3443
