Chemical biology hinges on multivalent molecular tools that can specifically interrogate and/or manipulate cellular circuitries from the inside. The success of many of these approaches relies on molecular tools that make it possible to visualize biological targets in cells and then isolate them for identification purposes. To this end, click chemistry has become in just a few years a vital tool in offering practically convenient solutions to address highly complicated biological questions. We report here on two clickable molecular tools, the biomimetic G-quadruplex (G4) ligands MultiTASQ and azMultiTASQ, which benefit from the versatility of two types of bioorthogonal chemistry, CuAAC and SPAAC (the discovery of which was very recently awarded the Nobel Prize of chemistry). These two MultiTASQs are used here to both visualize G4s in and identify G4s from human cells. To this end, we developed click chemo-precipitation of G-quadruplexes (G4-click-CP) and in situ G4 click imaging protocols, which provide unique insights into G4 biology in a straightforward and reliable manner.
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