An interdisciplinary team of researchers from Bath, Oxford and Hamburg has discovered a new endogenous cellular molecule, which could lead to the development of new drug candidates for autoimmune and metabolic disorders.
The team has been working for some years on a potential new drug target, the Transient Receptor Potential Melastatin 2 (TRPM2) channel. Previously, it had been assumed that the channel is activated by a structurally similar nucleotide (adenosine 5ʹ-diphosphoribose, ADPR). However, this new work suggests that the structurally-related 2′-deoxy-ADPR may actually be the true activator.
The TRPM2 channel is found mainly in the immune system and the brain where it has been linked to Alzheimer’s disease. Its activation lets cations, including calcium, move into the cell. It is involved in insulin secretion, immune cell responses and activation of the inflammasome. This means it may have a role in a number of autoimmune and metabolic disorders such as gout, obesity and diabetes.
The team used organic synthesis to design chemically-modified ADPR analogues with systematic changes in structure. Each new analogue was evaluated biologically to reveal the effects of each change. 2′-Deoxy-ADPR was identified, surprisingly, as being much more active than ADPR.
These results could help scientists to understand TRPM2 channel activation and its role in disease and may lead to the development of new drug candidates.
Lead author Professor Barry Potter said: “This new paper represents the pinnacle of many years of intense work and is one of the latest fruits of a UK-German collaboration in Cellular Signalling that has now extended over more than 20 years. Such work demonstrates the power of interdisciplinary research and that combining synthetic chemistry with cell biology can be highly synergistic.”
Dr Joanna Watt (pictured left), who synthesised the new molecules with Dr Christelle Moreau from the Department of Pharmacy & Pharmacology said: “I’m very interested to see what happens when other scientists study 2′- deoxy-ADPR in their biological systems. It is exciting to think that this might be a new second messenger. I hope that this discovery will lead to a better understanding of TRPM2 activation, and ultimately to treatments for related diseases.”
The research, published in the top-ranked journal Nature Chemical Biology, is the result of a long term collaboration between medicinal chemists at Bath and Oxford, led By Professor Barry Potter as well as biologists and biochemists from University Medical Center Hamburg-Eppendorf in Germany.
Source: University of Bath