Abstract
Chemical biology may provide useful small molecule probes that can contribute to advancing stem cells therapeutic application and the still challenging GPCR drug research field. In this context, in this thesis we focus on the development of chemical probes to the modulation of neural stem cells (NSCs) and, in parallel, to the characterization of the recently discovered P2Y14 receptor (P2Y14R). Particularly, the first application deals with pursuing a knowledge-based phenotypic approach (i) and a functionalized congeners approach (ii). Strategies (i) and (ii) have been conducted in parallel with the deliberate aim of identifying critical targets/pathways involved in NSCs differentiation and starting points for the development of new drugs. Particularly, a focused library of chemical probes has been designed and synthesized. An experimental pipeline, evaluating hepato- and neuro-toxicity, neuroprotection and proliferation in cell lines and primary neurons has been used for prioritizing compounds with better chances to be further investigated in the NCS phenotypic assay (i). In parallel, the application of the functionalized congener approach has allowed to design fluorescent, multi-target and polyamine congeners of the selected chemical scaffold (ii). Regarding the chemical biological approach towards P2Y14R, we have recently achieved promising results that could aid in unveiling its pharmacological potential in diabetes and inflammation. In particular, we have used structural insights of the recently obtained structural information of P2Y14R to discover a new scaffold for P2Y14R antagonists. In addition, two fluorescent probes (agonist and antagonist) have been developed and their utility to detect P2Y14R using fluorescence microscopy and flow cytometry has been also successfully demonstrated. Collectively, these results provide initial clues to our understanding of stem cell biology and P2Y14R pharmacology, and could inspire powerful pharmacological tools.
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