Structure and Function of Voltage-Gated Ion Channels and their Applications for Rational Drug Design

Sodium channels are membrane proteins which enable the regulation and flow of sodium ions across cell membranes. They are found in all eukaryotic organisms and a range of bacteria. In humans they exhibit a wide range of functions in the healthy organism, and are the targets for many pharmaceutical drugs for treatment of neurological and cardiac diseases. In insects they are the target sites of many insecticides, and also the source of development of resistance. This proposal is to determine the crystal structures of a number of natural and mutant sodium channels and related ion channels, and compare their structures with functional studies to better understand the means by which the channels open and close and selectively translocate sodium ions. By examining complexes of these channels with actual and potential drugs and ligands, this should enhance the rational development of new and highly specific insecticides and pharmaceuticals.

Voltage-gated sodium channels are responsible for transmembrane sodium ion conduction and, in eukaryotes, for electrical signalling in excitable cells. Their opening represents the first step in the action potential and they are key targets for the development of pharmaceutical drugs as well as novel and specific insecticides and mitocides. Sodium channels are also present in a wide range of prokaryotes, where they have roles in motility and chemotaxis. Related voltage-gates ion channels with different selectivity profiles are also found across the eukaryotics/prokaryotic spectrum and include roles such in diverse functions as fertilisation and sensation. This proposal aims to use a range of molecular biology, crystallographic, biophysical and electrophysiological techniques to define the structure and molecular bases of their gating, selectivity and drug/ligand interactions, to enhance our understanding the molecular basis of insecticide resistance, and to aid in the rational design of highly specific pharmaceuticals.

The potential public and economic impacts of this research are manifold, because sodium and other ion channels are essential components in human health and in agriculture. The beneficiaries will include both the commercial private sector, especially the pharmaceutical and agricultural industries (and hence the economy) and the public (by enhancing quality of life and productivity).

Impact on the Economy:
The pharmaceutical market for specific and highly efficacious sodium channel inhibitors/modulators is enormous, because the potential number of people with either chronic or acute pain is vast. It is for this reason that big pharma companies, as well as many smaller biotech companies have active programmes for the development of sodium channel-targeting drugs. The availability of the structures of crystalline complexes of sodium channels with ligands whose activity profiles have been defined in parallel with the structural studies, should have a dramatic impact on the initial and refinement phases of new drug design. Furthermore, the plethora of diseases (epilepsy, heart disease, myotonia, etc.) related to sodium channel misfunctioning in other tissues means that drug company development programmes in these areas should also benefit from the availability of drug/channel complex structures, especially as they should enable comparative modelling studies of homologous isoforms to better enable specific targeting for treatments without side effects resulting from broad-based sodium channel inhibitors.
There is also a very considerable market for species-specific insecticides and mitocides. Sodium channels are the targets for the pyrethroid compounds currently on the market, and were the targets of DDT, which ultimately produced significant resistance in the field. Knowledge of the binding site interactions for both of these types of compounds and for other new insecticides in development should enable the development of more specific insecticides/mitocides and ones that may be less likely to development resistance, both features of which could be important economically for the commercial sector.

Impact on the Public:
An essential aspect of "quality of life" is the ability to live pain-free. Sodium channels are causally associated with pain perception in humans and are currently the targets of a number of marketed pharmaceuticals. The availability of a sodium channel/drug complex structure should have a major impact on the design and development of new drugs to treat pain, and hence directly on the quality of life of the general public. The development of new and more specific drugs to treat neurological diseases such as epilepsy and various cardiovascular diseases will also benefit significant segments of the population.
In addition, the ability to more efficiently produce crops not destroyed by insects, but with more specifically targeted insecticides that do not harm either humans or plants, would also have a major quality of life factor in the ability to produce crops more effectively without harmful side effects to farmers and the environment.