According to scientists from the Medical Research Council (MRC) Laboratory of Molecular Biology in Cambridge, UK, a new drug discovery system can be used to target phosphatases (a family of enzymes) that are mostly considered to be ‘undruggable’.
Neurons
The research, which has been published in Cell, has demonstrated the capabilities of a new system to identify a molecule that could successfully target a phosphatase to reduce the accumulation of Huntington’s disease-associated proteins in the brains of mice.
These findings mean that scientists could then screen for drugs capable of targeting specific phosphatases, which has been previously difficult as the functional part that cuts off phosphate groups is common to all phosphatases, so drugging one phosphatase inhibits hundreds of them and kills cells.
“For decades, with no way to selectively target phosphatases, research into them has lagged behind kinases and they’ve been described as ‘undruggable’,” explained Dr Anne Bertolotti from the MRC Laboratory of Molecular Biology, who led the study. “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.”
This new research builds on previous work by the same scientists in which they created functional synthetic versions of phosphatase proteins. These synthetic phosphatases are then 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 was then tested in cells grown in a dish to check it was safe before testing in mice started.
A mouse model of Huntington’s disease was used as similarly to other neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, it features misfolded proteins that accumulate in cells in the brain. It was hoped that by slowing down a cell’s production of proteins would mean ‘its quality control machinery’ would have more capacity to clear up the misfolded proteins.
To slow down the protein production, the scientists targeted a specific phosphatase (PPP1R15B). Using the new drug discovery platform, they found a molecule called Raphin1 that only targeted that specified phosphatase.
On testing Raphin1 in the mouse model, it was shown to be able to cross into the brain where it reduced the accumulation of the disease-associated misfolded proteins in neurons. However, the researchers emphasized that this is early stage work with further study required to test if the drug will be safe and effective in humans or not.
“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,” summarised Bertolotti. “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.”