We are interested in mechanosensitive small-molecule fluorescent probes to image physical forces in living systems. This project has been initiated 2010, the first operational Flipper-TR® probes have been commercialized 2018. They operate based on twisted dithienothiophene push-pull dimers. Their mechanical planarization shifts excitation to the red and increases fluorescence lifetime. In living cells, increasing membrane tension is reported as increasing lifetime in FLIM images, and vice versa. Today, flipper probes that image tension in plasma membranes, mitochondria, ER and lysosomes are commercialized, flippers for early endosomes exist. HaloFlippers covalently attach to HaloTags expressed in the membrane of interest (MOI). SupraFlippers can be released in the MOI by chemical stimulation (operating on RUSH-type streptavidin biotechnology). Current emphasis is on HydroFlippers for the simultaneous imaging of membrane de/hydration and de/compression by triexponential FLIM image reconvolution, PhotoFlippers to release in the MOI with light, and blinking flippers for super-resolution microscopy.
Beyond these ongoing efforts to drive flipper probes toward perfection, we continue to explore alternative molecular design strategies for force imaging in live cells, and engage in diverse collaborations focusing on specific challenges.
These projects respond to a fundamental need in the life sciences waiting for solutions from chemistry, and it is satisfying see the fundamental principles from supramolecular chemistry providing the solution. A concise introduction of the emergence of flipper probes can be found in Bull. Chem. Soc. Jpn. 2020, 93, 1401–1411.
Methods: These projects generate much expertise in total synthesis. Probe characterization involves spectroscopy (absorption / fluorescence) and microscopy studies (FLIM, CLSM) in solution, vesicles (LUVs, GUVs), and in cells (co-localization, mask technology, FLIM methods, etc).
Collaborations: These projects connect to the NCCR Chemical Biology, with close collaborations with other members, NCCR group meetings and retreats. Interdisciplinary (post)doctoral studies in both chemistry and biology groups are possible. They also offer optional in-house collaboration possibilities with regard to computational chemistry and ultrafast photophysics.
"Science behind the scenes: The story of the Flipper probes development" by Margot Riggi
Some recent graphical abstracts: