The general objective of this project is to find conceptually innovative ways to deliver cargos into cells. Three distinct strategies are currently explored, all invented in this group: 1) Strain-promoted thiol-mediated uptake, 2) cell-penetrating poly(disulfide)s and 3) activators of cell-penetrating peptides.
Strain-promoted thiol-mediated uptake operates with highly strained cyclic disulfides. Release of this tension upon disulfide exchange with thiols on cell surfaces covalently links the transporter to the membrane and initiates uptake along so far unknown routes. Increasing ring tension results in increasing uptake: the AspA tag (derived from asparagusic acid) with a CSSC dihedral angle of 27° is good, while the most recent epidithiodiketopiperazine (ETP) tag with supreme tension near 0° is outstanding. Results with strain-promoted thiol-mediated uptake of fluorophores, peptides, liposomes and polymersomes are exceptionally promising. They call for comprehensive evaluation of extreme chalcogen chemistry for cellular uptake, development of interfacing technologies (biotin-streptavidin technology, bio-orthogonal chemistry, etc) and applications to cargos in the broadest sense (proteins, RNA, DNA, nanoparticles, etc).
Cell-penetrating poly(disulfide)s (CPDs) operate with a hybrid mechanism combining thiol-mediated uptake with the counterion-mediated uptake known from cell-penetrating peptides (CPPs). We successfully applied CPDs to the delivery of proteins (antibodies, nanobodies, etc), nanoparticles (quantum dots, etc), and so on. Compared to CPPs, CPDs are less toxic and more efficient in delivering the cargos to the cytosol.
Activators of cell-penetrating peptides are of interest to explore repulsion-driven ion-pairing interactions at work. Recent progress includes the integration of ionpair-π interactions and fluorophiles.
The discovery of new, general and reliable ways to enter cells promises solutions for one of the most persistent challenges in the life sciences, including public health. This is a very exciting perspective.
Methods: This project is ideal for those who are interested in combining substantial multistep synthesis with (optional) experience in polymer chemistry (GPC, DLS, etc) and biochemical methods (gel shift, cell culture, flow cytometry, confocal microscopy, etc). It can also accommodate PhD students and postdocs with biochemistry background and with interest in minimal exposure to organic synthesis.
Collaborations: These projects connect to the NCCR Chemical Biology and the NCCR Molecular System Engineering, with close collaboration with other members, NCCR group meetings and retreats. Interdisciplinary (post)doctoral studies in both chemistry and biology groups are possible.