We are interested in finding fundamentally new ways to enter into cells. Three distinct strategies are currently explored, all invented in this group: 1) Cellular uptake mediated by extreme sulfur and selenium chemistry, 2) cell-penetrating poly(disulfide)s (CPDs), and 3) activators of cell-penetrating peptides (CPPs). Integrating lessons from supramolecular chemistry, these approaches focus on dynamic covalent disulfide and diselenide chemistry, supported by dominant repulsion-driven ion pairing and more surprising ionpair-π interactions.
The idea with extreme sulfur and selenium chemistry is to maximize both selectivity and speed of dynamic covalent oligochalcogenide exchange on the way into cells, from surface to cytosol. Strain-promoted thiol-mediated uptake has been introduced in 2015, disulfide ring tension maximized in 2017, the shift to diselenides accomplished in 2018 (dithiolanes < epidithiodiketopiperazines (ETPs) < diselenolanes). The ongoing efficient delivery of probes, peptides, proteins, liposomes, polymersomes, quantum dots calls for bolder adventures with extreme sulfur and selenium chemistry, refined interfacing (biotin-streptavidin, bioorthogonal chemistry) and challenging substrates.
Cell-penetrating poly(disulfide)s (CPDs) operate with a hybrid mechanism, combining dynamic covalent disulfide exchange chemistry with the repulsion-driven ion pairing known from cell-penetrating peptides (CPPs). We are constantly developing new CPD architectures and use them to deliver proteins (antibodies, nanobodies, etc), nanoparticles (quantum dots, etc), artificial metalloenzymes as gene switches in designer mammalian cells, and so on. The efficient cytosolic delivery of functionalized quantum dots is a fine example for the type of challenges in biology that can be addressed with fundamentally new ways to enter into cells. Alternative chemical methods do not exist. The discovery of new, general and reliable ways to enter cells thus promises solutions for one of the most persistent challenges in the life sciences, including public health. This is a very exciting perspective.
Methods: These projects generate expertise in multistep synthesis, (optional) polymer chemistry (GPC, etc) and biochemical methods (uptake analysis, cell culture, flow cytometry, confocal microscopy, etc). They can also accommodate PhD students and postdocs with biochemistry background and preference for limited exposure to organic synthesis.
Collaborations: These projects connect to the NCCR Chemical Biology and the NCCR Molecular System Engineering, with intense collaboration with other members, NCCR group meetings and retreats. Interdisciplinary (post)doctoral studies in both chemistry and biology groups are possible.
Some recent graphical abstracts: