Investigation of the target of metformin

Metformin, which is known chemically as a biguanide, took more than five decades to become one of humanity's most widely used medicines. It is the medicine of choice for type 2 diabetes and is under investigation for use in a much wider variety of diseases associated with age-related metabolic problems. Many of the beneficial clinical effects of metformin within the body are known but unfortunately it is still unclear how metformin triggers these effects and why it doesn't always work. This is the missing piece of the jigsaw that we are providing here. The approach in the work leading up to this proposal has been to modify the chemical structure of metformin, in order to work out which bits of metformin are required for its actions on the cells in our body. Our new finding is that metformin's effects are lost when we interfere with the drug's copper-binding properties. Metformin itself has been known to bind copper for over a century but our latest data suggests that metformin actually targets copper as a key part of its therapeutic effects, something we now wish to understand in more detail. An unusual and striking aspect of this interaction is that metformin forms unusual 'pseudoaromatic' structures with copper that actually change the shape of the metal. In simple terms, the key distinction between other known metal-binding drugs and metformin can be understood most easily by analogy with The Sun and The Wind in Aesop's fable for children, whose lesson is 'Persuasion is better than force'. Other drugs (The Wind) attempt to force metals out of protein binding sites simply because they bind the metal more strongly, while instead guileful metformin (The Sun) acts first by inducing the protein to loosen its grip on the metal by altering the metal coordination environment. Our research will determine whether this trick is important for effects of metformin on muscle and liver cells. By developing a better understanding of one of the agents currently available, this proposal will pave the way to the development of better agents against age-related metabolic disease in future.

The biguanide metformin is the drug of choice for treatment of type 2 diabetes (T2D) and is under investigation for use in a variety of other age-related disease states. Used in T2D, metformin is associated with reduced risk of cardiovascular and other mortality when compared with other treatment regimes. Around one third of individuals prescribed metformin discontinue use shortly after starting the drug due to gastrointestinal side effects and therefore it would be highly desirable to develop metformin-like compounds with similar properties. Unfortunately however, the mechanism of action of metformin remains incompletely understood and the identity of its proximal target, which would greatly aid development of such drugs, is unknown. In the current work we wish to follow up new evidence that we have obtained that an important direct target of metformin is copper. Previously, we investigated how metal ions can modify the activity of drugs and in our preliminary studies we have gathered strong evidence that copper, whose interaction with metformin has been known for over a century, is required for specific cellular actions of metformin that are linked to its beneficial therapeutic effects. In the current study we aim to elucidate the precise role of copper in metformin action using unique chemical tools and a variety of techniques including western blotting, gene expression analysis and microscopy. This research will establish which effects of metformin are copper-dependent, and of these which depend on metformin's unusual 'pseudoaromatic' metal-binding mode. Research to identify the target of metformin will ultimately facilitate development of new drugs for the treatment of diseases associated with age-related metabolic dysfunction, consistent with MRC's strategic research priority "Living a long and healthy life"

This proposal forms part of a continued effort to maximise the impact of the group's research. In the work leading up to the current proposal the group has moved away from experimental signalling compounds that are of specialist interest only, to embrace therapeutically useful agents whose mechanism is incompletely understood. The aim of this application is to learn more about the action of one of these agents on cell physiology, which promises to illuminate a path towards the development of better therapeutic agents in the future. Dysregulation of insulin signal transduction is increasingly understood to affect organismal ageing in organisms from C.elegans and Drosophila to mammals, research that fits well with MRC's current strategy to support research towards living a long and healthy life. The current proposal will contribute towards MRC's portfolio in this area by enabling the identification either of cellular signalling mechanisms and/or chemical agents that can then be investigated in vivo for utility in prolonging lifelong health and wellbeing

Given sufficient long-term support, a portfolio of research in this area is likely to have several beneficiaries who will benefit as outlined below:

(i) Biotech and pharmaceutical companies, who could develop any new agents or targets that we identify. A successful example of this is Sirtris in the US, a company focussed on discovering and developing proprietary drugs with the potential to treat diseases associated with aging which was recently sold to GSK for nearly $1 Billion. There is clearly an outstanding opportunity for the UK to improve its competitiveness in this area, given the breadth and depth of relevant experience in UK labs. If a similar biotech company developed in the UK, this would also provide employment opportunities for appropriately qualified PDRAs coming through these UK labs.

(ii) The general public, UK government and NHS will ultimately benefit from agents capable of prolonging the 'healthspan.' Longevity is increasing rapidly in the UK and elsewhere but this will only provide benefit to individuals and be affordable in terms of taxation and health care if the extra years are healthy years.