Designing new drugs to treat MS

Associate Professor Richard Hughes

The University of Melbourne, VIC

| A cure via repair and regeneration | Epidemiology | Genetics | Neurobiology | Project | 2017 | Investigator Led Research |
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Summary

MS results from the loss of myelin, the insulating sheath around nerve fibres, in the brain and spinal cord. Brain-derived neurotrophic factor (BDNF) is one of the proteins that controls the growth of myelin during development and is also able to repair myelin after it has been damaged. As such, BDNF could form the basis of a new treatment option to repair myelin in MS. However, since BDNF is a large protein and is broken down by the body very quickly, it cannot itself be used directly as a treatment.

In an attempt to overcome these limitations, Associate Professor Hughes and his team are developing smaller molecules which mimic the function of BDNF but might also be suitable as therapies.  Associate Professor Hughes and his team were previously funded by an MS Research Australia Incubator Grant to develop a synthesis method for a compound called ‘TDP6’, which mimics BDNF and is able to repair myelin.

This project is further investigating the precise way that this new compound repairs myelin and also determining the chemical and pharmacological profile of this potential drug, important further steps in turning TDP6 into a drug for treatment. They also plan to make improvements to the current TDP6 design which will make the compound smaller and more potent. The team will also develop other mimics of BDNF for further investigation as a treatment option for MS.

Repair of myelin damage is the holy grail of MS research, as treatments which promote repair would be able to restore function that has been lost and provide therapeutic options for people with progressive forms of the disease.

Progress to Date

Associate Professor Hughes and his team have redesigned the TDP6 molecule to improve its structure. Using a cutting-edge chemistry technique in a completely new way, they substituted some of the molecular components of the compound with more efficient chemical connections. This will make this version of TDP6 more effective as a treatment for MS and will considerably refine and simplify the way it is made, an important consideration if it is to be scaled up as a therapy for MS.

Associate Professor Hughes has made seven versions of TPD6 with different molecular components and has carried out many experiments to determine the optimal conditions for the reaction. He has begun comparing the actions of these new versions of the drug to the original form in different biological pathways, including their ability to remyelinate.

Since this is a completely novel use of the chemistry, Associate Professor Hughes and his team have thoroughly investigated the chemical reactions and have also published this work in a scientific journal. This work has also been presented at national conferences and has underpinned a PhD project and formed part of the work undertaken by a postdoctoral researcher.

Publications

  • Lin Q, Hopper D, Zhang H, Sfyris Qoon J, Shen Z, Karas JA, Hughes RA & Northfield SE. “1,3-Dichloroacetone: A Robust Reagent for Preparing Bicyclic Peptides” ACS Omega, 2020, 5: 1840-1850
  • Fletcher JL, Wood RJ, Nguyen J, Norman EML, Jun CMK, Prawdiuk AR, Biemond M, Nguyen HTH, Northfield SE, Hughes RA, Gonsalvez DG, Xiao J & Murray SS. “Targeting TrkB with a brain-derived neurotrophic factor mimetic promotes myelinrepair in the brain.” Journal of Neuroscience, 2018, 38: 7088-7099

Updated: 11 June 2020

Updated: 05 March, 2017

Investigator

Co-investigator

Grant Awarded

  • Project Grant

Total Funding

  • $165,000

Duration

  • 4 years over 2017 - 2020

Funding Partner

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