International Centre for Neurotherapeutics

interests and expertise

Interests and Expertise 

 

Success continues to be achieved in 3 main inter-related themes, facilitated by the experimental expertise developed over the years and the available sophisticated facilities including advanced equipment:

 

  1. 1.    Deciphering molecular events in the ubiquitous process for the release of chemical transmitters/pain mediators from different nerve types, by Ca2+-regulated exocytosis, which underlies all of the main bodily functions.

It involves key proteins called SNAREs which are potently and selectively inactivated by unique proteases, as in botulinum neurotoxin A.  This forms the basis of its widespread clinical use for treating up to 100 over-secretory conditions.  Using protein engineering, the therapeutically-beneficial characteristics of this molecule have been combined with those of variant subtypes in proprietary chimeras and hybrids that exhibit improved versatility and efficacy for new medical applications.  These are best exemplified by a newly-developed, potent and long-acting form that effectively relieves chronic pain in pre-clinical studies; international patents for these innovative biotherapeutics have been granted recently.

 

  1. 2.    Normalising dysfunctional conduction of nerve signals in a model of multiple sclerosis with a novel, selective blocker of a culprit K+ channel.

Our earlier elucidation of the oligomeric, subunit and primary structures of a particular group of voltage-sensitive K+ channels in brain membranes has allowed their re-creation in vitro by recombinant technologies.

 

A major defect in neural signaling in multiple sclerosis arises from auto-immune mediated loss of the insulating myelin sheet from axons.  On mimicking this demyelination in vivo, we discovered that a particular K+ channel member becomes elevated and spreads out from its normal restricted location at nodes of Ranvier.  Most importantly, the hyper-polarising influence of this ‘rogue’ K+ current counteracts the propagation of electrical signals along the non-insulated nerves.

 

Guided by this outcome, a chemi-informatic strategy was adopted with Dr. K. Nolan (Chemical Sciences, Dublin City University) and Dr. G. Kinsella (Dublin Institute of Technology) that culminated in a small, organic blocker of this protein being successfully modelled (Fig. upper).  Reassuringly, after synthesis and purification, this dipyrromethane adduct was shown to interact intimately (Fig. lower) and inhibit selectively this K+ channel, when expressed on the surface of mammalian cells.  Accordingly, in preliminary experiments performed in collaboration with Drs. M. Pickering and C. Herron at University College Dublin, this blocker appears to raise signal conduction by demyelinated axons from an in vivo model of multiple sclerosis.  These data provide proof-of-principle for this promising therapeutic and, thus, further refinement and development are warranted.

 

 

 
 

Model of the blocker (in yellow) interacting with the external mouth of  the Kv1.1 channel ion filter (upper), an amplified representation of the interactive groups identified on the inhibitor and amino acids from the multiple subunits of the protein (lower).

 

 

 

 

 

Link to blocker model:

Model of blocker.pptx