Strategies and tactics for subcellular targeting of small molecule zinc sensors

Zinc(II) ions play manifold roles in human health; dysregulation of zinc homeostasis has been implicated in a number of diseases and pathological conditions. Because zinc(II) is spectroscopically silent, it cannot be detected directly by conventional fluorescence microscopy. As a result, investigators seeking to image zinc(II) in biological systems frequently turn to small-molecule fluorescent sensors that selectively respond to the presence of the ion. This tutorial review describes methods for delivering such small-molecule probes to discrete subcellular locales. Attention is given to the preparation of conjugates in which well-characterized sensors are tethered to molecular homing moieties that accumulate in particular organelles or other compartments. Hybrid approaches that entail enzyme-mediated localization of synthetic constructs, as well as other novel techniques, are also discussed. The various fluorescent probe targeting methods described here enable opportunities for new discoveries in zinc biology.