Epilepsy and other associated seizures are a significant health concern, occurring in an estimated 1-2% of the world’s population. Treatment is commonly through chronic administration of antiepileptic drugs (AEDs), many of which have severe side-effects with prolonged use. Drug treatment also has the limitation in that only about two-thirds of epilepsy patients exhibit marked improvement. For the remaining third, no effective drug treatment is available. Novel cellular targets are urgently required to catalyse the development of more favourable drugs in order to provide better therapeutic outcomes.
We have identified the protein Pumilio as an attractive target for AED design. Pumilio is a well-characterised repressor of translation, present in all animals, that acts by binding to mRNA transcripts. This includes mRNAs encoding voltage-gated sodium channels in neurons. Translational repression results in decreased sodium channel protein synthesis and subsequent reduced action potential firing. This activity is consistent with many existing AEDs but, importantly, is achieved by novel means. Using a cell-based reporter screen, we have identified a chemical compound that potentiates the activity of Pumilio and is strongly anticonvulsant in seizure models. This compound has significant potential to generate a novel class of AED.
The PhD project will involve chemical synthesis of organic compounds (supervised by Dr. Freeman) to increase anticonvulsant potency along with desirable drug-specific criteria: solubility, stability and non-toxicity. Compounds will first be screened in a cell-based screen and hits will be tested for anticonvulsant properties in Drosophila and zebrafish seizure models (supervised by Prof. Baines).
The ideal candidate will have a good understanding of organic/medicinal chemical synthesis and an appreciation of the drug development process. Knowledge of epilepsy and neurophysiology will also be advantageous. However, full training will be provided in drug screening and testing.
This project has a Band 3 fee. Details of our different fee bands can be found on our website (https://www.bmh.manchester.ac.uk/study/research/fees/). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/).
Informal enquiries may be made directly to the primary supervisor.
Lin WH, He M and Baines RA (2015) Seizure suppression through manipulating splicing of a voltage-gated sodium channel. Brain 138:891-901.
Cunliffe VT, Baines RA, Giachello CNG, Lin WH, Morgan A, Reuber M, Russell C, Walker MC and, Williams RSB (2015) Epilepsy Research Methods Update: Understanding the causes of epileptic seizures and identifying new treatments using non-mammalian model organisms. Seizure 2015 Jan; 24C:44-51.
Lin WH and Baines RA. (2015) Regulation of membrane excitability: a convergence on voltage-gated sodium conductance. Mol Neurobiol. 51:57–67.
Alnabulsi S, Santina E, Russo I, Hussein B, Kadirvel M, Chadwick A, Bichenkova EV, Bryce RA, Nolan K, Demonacos C, Stratford IJ and Freeman S. Non-symmetrical furan-amidines as novel leads for the treatment of cancer and malaria. European Journal of Medicinal Chemistry, 2016, 111, 33–45.
Daniels MJD, Rivers-Auty J, White C, Yu S, Schilling T, Spencer NG, Watremez W, Fasolino V, Baldwin AG, Freeman S, Latta C, Jackson J, Fischer N, Koziel V, Pillot T, Bagnall J, Pazek Pawel, Galea J, Lawrence C, Harte M, Eder C and Brough D. 2016. Fenamate non-steroidal anti- inflammatory drugs are NLRP3 inflammasome inhibitors. Nature Communications – accepted 7/16.