The Operating Theatre Journal Digital Edition September 2018

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New system can identify drugs to target “undruggable” enzymes critical in many diseases 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 MRC Laboratory of Molecular Biology 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. Targeting Huntington’s disease 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. Left: Huntingtin protein (green) accumulated in the cells from the brains of mice given a placebo. Right: Showing reduced build-up of huntingtin protein in cells from mice treated with Raphin1. Credit: Krzyzosiak et al./Cell 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.” The study was funded by the MRC, the European Research Council, the Human Frontier Science Program, EMBO and the Swiss National Science Foundation. 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 Huntington’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. ----S ubscribe to the OTJ 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. Discover more Online!! Join our FREE mailing list at www.otjonline.com and stay in touch with News and reviews. Delivered to your door every month It’s easy to subscribe, just visit our website at www.otjonline.com and pay via Card or Paypal. Have your own personal copy of the Operating Theatre Journal Subscribing to the OTJ costs just £14.00 per year to cover delivery in the UK, For corporate and overseas customers just £24.00 Visit: www.otjonline.com/subscription.php or Email: admin@lawrand.com 14 THE OPERATING THEATRE JOURNAL www.otjonline.com ---- --------------------------------
Ward Nurses MercyAscot, Auckland, New Zealand Make Auckland your new home… and work for MercyAscot Hospitals, one of New Zealand’s largest providers of private surgical facilities! We have opportunities available within our Inpatient Services Wards. You will need: • Minimum of 24 month’s experience in a specialised ward environment in the United Kingdom health system • Current APC and NZ Nursing Council (NZNC) registration or are eligible to gain registration with the NZNC Our Inpatient Services teams care for patients who have undergone various Orthopaedic, Cardiac, neuro surgical and general surgical procedures, as well as some gynaecology and plastics. Under the leadership of a dedicated Charge Nurse Manager, the teams provide a positive experience and outcome for our patients. The variety of patients we care for and the opportunity to interact with some of Auckland's leading Specialists, providing direct input into patient care, makes the nature of this role unique and challenging. Full orientation is given to all new employees and specialist Clinical Nurse Educators provide support to the nursing team to keep up to date with the latest trends in general surgical nursing specialities. MercyAscot provides support for professional development should you wish to develop your skills and knowledge further. Why MercyAscot? • New Zealand's largest private surgical facility with 22 theatres across three sites including ICU • MercyAscot prides itself on servicing high acuity specialities. • We provide our staff with a supportive working environment, autonomy of practice, competitive remuneration rates, free on-site car park, smart easy-care uniforms, and a Christmas close-down that allows you to enjoy the festive season with your friends and family • We are committed to ongoing professional development and full orientation is given to all new employees • We strive to provide an excellent service for all our patients and enjoy working alongside many of Auckland's leading surgical specialists. So don't just take on a job, create your career… Make MercyAscot your Employer of Choice! Click the link to apply today. Whether you are looking for work/life balance or career progression, MercyAscot has a place for you!
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