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 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.
The study lead, 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.
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.
In cells, Raphin1 caused a rapid and transient accumulation of its phosphorylated substrate, resulting in a transient attenuation of protein synthesis. In vitro, Raphin1 inhibits the recombinant R15BPP1c holoenzyme, but not the closely related R15A-PP1c, by interfering with substrate recruitment.
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 emphasize that this is early stage research and more work is needed to test if the drug will be safe or effective in humans.
The author 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."
https://mrc.ukri.org/news/browse/drugs-to-target-undruggable-enzymes-critical-in-many-diseases/
https://www.cell.com/cell/fulltext/S0092-8674(18)30798-0
Latest News
Father's gut microbes affec…
By newseditor
Posted 08 May
A new brain circuit in mice…
By newseditor
Posted 08 May
Mechanism of choline entry…
By newseditor
Posted 07 May
Link between UTI and breast…
By newseditor
Posted 07 May
Sleep resets brain connections
By newseditor
Posted 07 May
Other Top Stories
A non-invasive, adhesive patch to monitor blood glucose
Read more
Specific bacteria in the small intestine are crucial for fat absorp…
Read more
Variation in a gene affects how some women store fat – and ups thei…
Read more
Why alcohol, sugar lead to thirst
Read more
Why is it harder for females to gain weight?
Read more
Protocols
Single-cell adhesive profil…
By newseditor
Posted 07 May
Parasympathetic neurons der…
By newseditor
Posted 07 May
Non-invasive measurements o…
By newseditor
Posted 05 May
A validation strategy to as…
By newseditor
Posted 04 May
Generation of rat forebrain…
By newseditor
Posted 03 May
Publications
Paternal microbiome perturb…
By newseditor
Posted 08 May
Truncating NFKB1 variants c…
By newseditor
Posted 08 May
Synaptotagmin-11 facilitate…
By newseditor
Posted 08 May
Astrocytic Slc4a4 regulates…
By newseditor
Posted 08 May
Diabetic retinopathy is a c…
By newseditor
Posted 08 May
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar