Cells send signals using small molecules called inositol phosphates and related messengers, and this team will build custom synthetic versions of those molecules to probe how the signals work and to test whether they can be turned into drugs. The problem is that many of these signalling molecules are poorly understood. For example, no one knows exactly how the messenger inositol trisphosphate opens its receptor, or what the mysterious higher phosphates IP7 and IP8 actually do. Without precise chemical tools, researchers cannot tease apart these mechanisms or find drug targets. If the project succeeds, it will produce a suite of synthetic molecules that can activate or block specific signalling pathways with high selectivity. Some of these compounds could become leads for drugs—for instance, a cell-permeable agonist of the TRPM2 ion channel might offer a new therapeutic approach, and a synthetic antagonist of the NAADP receptor could be tested in disease models. The work also targets the enzyme CD38, which makes several of these messengers, with structure-based inhibitor design. This is fundamental chemical biology. It will not deliver a drug tomorrow. But by revealing how cells use these ancient signalling molecules, it lays the groundwork for future treatments in areas such as inflammation, neurodegeneration, and cancer.
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We will apply tailored small molecules as tools and drug candidates in intracellular signalling. Multidisciplinary chemical biology will be driven, often with expert collaborators, by a unique focus on synthetic chemistry with structural biology, spectroscopy, computational chemistry, imaging, electrophysiology and enzymology. We will interrogate, ideally in atomic detail, roles of lower and higher inositol phosphates (IPs), phosphoinositides (PIs) and newer messengers cyclic adenosine 5-diphosp hate ribose (cADPR), adenosine 5-diphosphate ribose (ADPR) and nicotinic acid adenine diphosphate ribose 2-phosphate (NAADP). Key goals reflect two areas of equal endeavour: For IP/PIs: to illuminate how inositol trisphosphate activates its receptor, design and exploit specific agonists, partial agonists and antagonists, also with cellular permeability; we will unravel the structure-activity relationship (SAR) and therapeutic potential of an epigenetic histone deacetylase coregulator with IP surrogates to substitute and inhibit at the binding site; mechanistic and modulatory tools will target lipid phosphatases, explore the origins, significance and targets of IP5 and IP6, and the enigmatic higher IP7 and IP8; using structural biology we will develop our simplified synthetic surrogates for relevant enzymes and against IP-dependent bacterial exotoxins. For cADPR/ADPR/NAADP: stable synthetic templates will provide tools to identify the cADPR receptor in diverse systems and rational ise complex SAR; synthetic nucleotides will define the first agonist-antagonist TRPM2 SAR for ADPR to explore a therapeutic approach using a permeant ADPR-agonist; designed tools will address the NAADP receptor/binding protein with our first generation synthetic antagonist iterated towards disease models; structure-based inhibitor design for CD38 cyclase will be exploited to manipulate signalling pathways.
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