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"Development of selective antagonists and subtype selective ligands for the D-myo-inositol 1,4,5-trisphosphate receptors."

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Novel probes to study intracellular signalling

Understanding how cellular processes work often requires the design of molecules with activating or inhibitory activity on signalling pathways. In this context, European scientists combined in silico work with cell biology and chemistry to design and synthesise novel ligands.

Health

Inositol trisphosphate receptor (InsP3R) is a membrane protein that is primarily localised in the endoplasmic reticulum of cells. It gets activated by the intracellular messenger inositol trisphosphate and serves as a channel for calcium ions. It functions in the control of various cellular and physiological processes, including cell division, proliferation and apoptosis. The EU-funded SELECTIPROBE project set out to develop novel ligands to probe the role of the different InsP3Rs in intracellular calcium signalling. Such selective ligands would be useful in determining the particular role of each of the InsP3R subtypes in cellular function and disease such as heart arrhythmia and cardiac hypertrophy. In addition, the consortium wished to generate selective and potent non-inositol InsP3R antagonists to block the activity of the InsP3Rs in case of malfunction. For this purpose, scientists performed an in silico screen and through state-of-the-art technology they were able to identify promising lead compounds. These compounds were subsequently screened using the saturation transfer difference nuclear magnetic resonance technique for binding onto protein phosphate binding sites. The activity of the compounds was further determined using different cell-based assays. Scientists synthesised thiazolidinones and identified binding interactions with the galactosyl human serum albumin protein. They also performed X-ray crystallographic studies to delineate the 3D structure of three thiazolidinone compounds, and selected a group of molecules with putative inhibitory activity. These findings have triggered future modelling experiments in order to develop new structures and obtain the most effective inhibitors. It is anticipated that this work will help understand the role of the different InsP3Rs in health and disease.

Keywords

Intracellular signalling, inositol trisphosphate receptor, selective ligands, cellular function, thiazolidinone

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