Molecular Mechanisms for a Novel Class of Openers Targeting Voltage- and Calcium-activated Potassium Channels.

Fragile X syndrome (FXS) is the most common inherited form of mental disability. A novel class of compounds synthesized by Canbex Therapeutics shows beneficial effects on cognitive and behavioural deficits in an animal model of FXS. Additionally, these compounds have shown positive effects in the treatment of spasticity in a multiple sclerosis model, acting through the activation of voltage- and calcium-dependent potassium channels (BK channels). BK channels are widely expressed in the nervous system where they contribute to the repolarization of action potentials and afterhyperpolarization in neurons, beside regulating synaptic release of neurotransmitters. Their molecular make-up depends on the co-assembly of alpha, beta and gamma subunits that confer specific kinetic and pharmacological properties to the channels. BK channel dysfunction has been proposed to contribute to the neurological deficit in FXS.

Aims:
The main aim of this project is to define the molecular target and mechanism of action of the novel compounds develop by Canbex Therapeutics and optimise drug design for the treatment of neurological disorders. The results of this project will ultimately enable us to achieve the best possible pharmacological approach to the treatment of spasticity in multiple sclerosis and other neurological disorders that can be treated by targeting neuronal voltage- and calcium-dependent potassium channels, such as Fragile X syndrome.

Plan of investigation:
The action of the Canbex compounds will be studied by electrophysiology and in vitro pharmacology on recombinant and neuronal BK channels. On one hand, their effects will be investigated at the level of single neurons and whole circuits in brain slices from healthy and FXS-model animals. On the other, the identification of their molecular mechanism of action and primary target will lead us to define and model their binding site and potentially design, synthesize and test optimised derivatives.
We look for a student with a strong background in molecular and cellular biology and with excellent analytical skills, to be trained in molecular biology, electrophysiology on cell lines and neurons, in vitro pharmacology, drug synthesis and design, and computational and in silico modelling. The student will receive broad scientific training in a multidisciplinary environment, gaining valuable experience both in an academic and in an industrial setting.