Introducing deuterium for next generation chemical biology probes and direct imaging

The ideal microscopy experiment would take place in native cells without genetic engineering, with 3-dimensional resolution on the single molecule scale (<10 nm) by observing the endogenous molecule itself. I propose the introduction and use of deuterium (“deuterON”) as a general method for a multimodal approach, to i) synthesize a first-in-class deuterated cyanine (Cy) fluorophore for super-resolution imaging, ii) to design and test deuterated, next-level photoswitches to restore vision, and iii) use these probes and deuterated drugs for direct and bioorthogonal, spectroscopic imaging. In particular, deuterated Cys will allow stochastic reconstruction microscopy (STORM) by using near infra-red light to break new ground in protein localization in live tissue, opening the gates for thick sample imaging (~100 m axial) with retained super-resolution (~20 nm). In addition, deuterated azobenzene photoswitches will be designed to finally reach the indispensable, and to-date unobtained light sensitivity to remote control neural signalling in vivo. Lastly, the use of ""label-free"" labelling and imaging will be explored with deuterated drugs to observe drug uptake and metabolism by utilizing the unique properties of the carbon-deuterium bond in Raman spectroscopy. Coupled to a confocal microscope, deuterated drugs will be tracked in native and live cells, without any genetic engineering strategies, and on the molecule of interest itself, reducing perturbations and artefacts to a minimum. This ground-breaking approach holds promise to be generalizable to Chemical Biology disciplines, and as an unconventional, yet attractive and powerful method to design and synthesize next generation small molecule probes. Developing a pipeline for these aims will be a game changer, with ramifications for the life sciences, cell biology, drug development and with prospective translational impact.""