We are interested in conceptually innovative ways to enter into cells. Currently, all attention shifts toward thiol-mediated uptake as the method of choice to deliver directly to the cytosol. With the outbreak of the corona pandemic, we also started to explore inhibitors of thiol-mediated uptake as possible antivirals, and have found and patented promising anti-SARS-CoV-2 candidates. The recent finding that oligonucleotide phosphorothioates enter cells the same way further enhances scope and significance of thiol-mediated uptake.
Thiol-mediated uptake is interesting because it is so useful in practice but nobody knows have it really works. We see thiol-mediated uptake as central logic network that encodes for sending matter into cells, including pathogens. This possibly extraordinary importance makes us determined to map out the chemical space surrounding thiol-mediated uptake comprehensively. Central are the elucidation of dynamic covalent exchange cascades with cellular partners and the introduction of new cascade exchangers beyond cyclic oligochalcogenides, including pnictogen and tetrel relays. This also concerns more materials related ring-opening dynamic covalent polymerization on various templates or molecular walkers, and of course traceless click systems for easy use in practice, including oligonucleotide transfection. This rapidly growing topic also has room for pure biochemistry projects related to target identification by genetic engineering and proteomics. The perspectives emerging from the chemical space around thiol-mediated uptake have been developed in JACS Au 2021, 1, 710–728.
Methods: These projects generate expertise in multistep synthesis, dynamic covalent network analysis, polymer chemistry. Uptake, antivirals and network analysis benefits from state-of-the-art infrastructure from the NCCR (ACCESS platform; cell culture, including spheroids, HGM cells (CAPA assay for cytosolic delivery), automated high-content high-throughput microscopic imaging, genetic engineering, proteomics).
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: