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Drug Discovery System Designed to Identify Difficult Targets

Nerve cells in brain

Nerve cells in brain (NIH.gov)

27 July 2018. A lab in the U.K. developed a system for discovering new therapies that identify therapy targets linked to enzymes, some found in neurodegenerative diseases, previously considered too difficult to address. A team from the MRC (Medical Research Council) Laboratory for Molecular Biology in Cambridge, England describe the system in yesterday’s issue of the journal Cell.

Researchers led by molecular biologist Anne Bertolotti are seeking better treatments for neurodegenerative disorders such as Alzheimer’s and Huntington’s disease, as well as amyotrophic lateral sclerosis, or ALS. One hypothesis behind the onset of these diseases is the increasing prevalence of misfolded proteins and the build-up of these defective proteins, with the likelihood of this condition increasing with age. Bertolotti’s group studies the mechanisms contributing to protein defects, including those controlling phosphorylation, or the levels of phosphates in proteins, involved in a large number of cellular functions, with changes in phosphate levels often controlled by specific enzymes.

One of those enzymes is known as a phosphatase, which removes phosphates from proteins. While regulation of phosphatases is considered a promising strategy in principle for affecting phosphorylation in proteins, phosphatases up to now were considered too difficult to address with today’s drug molecules. Bertolotti and colleagues developed a screening process beginning with a technique called surface plasmon resonance, a non-invasive optical biosensing method that uses light to excite characteristic electrons returning oscillation patterns to identify specific molecules. In this case, the process yielded a phosphatase component called R15B with the potential to modify phosphate levels in proteins.

With R15B as the target, the researchers screened for protein molecules with the ability to inhibit only this component, returning a small molecule compound identified as Raphin1 that stops the actions of R15B. In lab cultures, the team found Raphin1 could temporarily limit the effects of R15B, and keep cells from producing a high volume of defective proteins. With defective proteins reduced, cells could function more normally and correct the effects of the defective proteins.

The researchers tested Raphin1 further in lab mice induced with Huntington’s disease, an inherited disorder in which nerve cells in certain parts of the brain degenerate. The condition is caused by a defect in a chromosome where a portion of the DNA repeats many more times than normal, and because the disease starts in the DNA, it is passed along from parents to children. The team found Raphin1, given to mice as an oral drug, can cross the blood-brain barrier, reduce phosphorylation, and limit production of the defective proteins responsible for Huntington’s disease.

The researchers believe their drug discovery process can be extended to other precise phosphatase targets previously considered undruggable. Precision targeting is important to prevent unintended adverse effects. “For decades,” says Bertolotti in an institute statement, “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.”

The authors filed for patents on their techniques. In addition, Bertolotti is a founder of the biotechnology company CamPhos Therapeutics Ltd. in Cambridge that began earlier this year.

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