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The Potter group has been part of an interdisciplinary and international research team that has discovered a new endogenous cellular molecule called 2′-deoxyadenosine 5'-diphosphate ribose (dADPR) that may play an important role as a chemical signal in autoimmune and metabolic disorders, such as obesity and diabetes.

2'-Deoxyadenosine 5'-diphosphate ribose (dADPR)

The research, published in Nature Chemical Biology, is the result of a long-term collaboration between medicinal chemists from the University of Oxford’s Department of Pharmacology and the University of Bath, led by Barry Potter, with biologists and biochemists at the University Medical Centre, Hamburg-Eppendorf in Germany.

The team has been working in collaboration for some years on a potential new drug target, the cellular ion channel Transient Receptor Potential Melastatin 2 (TRPM2). The TRPM2 channel is found mainly in the immune system and the brain where it has been linked to Alzheimer’s disease. Its activation allows cations, including calcium, to move into the cell. It is involved in insulin secretion, immune cell responses and activation of the ‘inflammasome’.

Previously, it was assumed that this channel is activated by a different molecule, adenosine 5'-diphosphate ribose (ADPR) – see Figure. The new work, however, suggests that dADPR may actually be the true activator and this was identified, surprisingly, as a having over 10 times higher activity than ADPR.                       

The Potter group used organic synthesis to design chemically-modified analogues that systematically probed the main structural motifs of ADPR. Each new compound was evaluated biologically to reveal how structural changes affected TRPM2 activation. While some were antagonists, surprisingly hardly any had any agonist activity.

Based on this the group also studied the mechanism behind the dADPR response, using, amongst many techniques, mass spectrometry on extracts from stimulated cells to prove that the molecule is indeed found in cells. They also demonstrated that dADPR can be produced by cellular enzymes using substrates available in cells. This leads to the intriguing suggestion that the true activator of TRPM2 may have been uncovered, potentially as an example of a new “second messenger” molecule, one of a very small group of compounds that carry chemical signals in cells. Further work is now underway to explore this idea.

These results could aid a better understanding of TRPM2 channel activation and its role in disease and may lead to the development of new drug candidates.

The UK work was funded by the Wellcome Trust to Professor Potter, who is a Wellcome Trust Senior Investigator and by a joint Wellcome Trust Project Grant with Hamburg.

2'-Deoxyadenosine 5'-diphosphoribose is an endogenous TRPM2 superagonist. R Fliegert, A Bauche, AM Wolf Perez, JM Watt, MD Rozewitz, R Winzer, M Janus, F Gu, A Rosche, A Harneit, M Flato, C Moreau, T Kirchberger, V Wolters, BVL Potter and AH Guse. Nat Chem Biol (2017) 13: 1036-1044.