We are interested to find new ways to enter cells. Building on much experience with cell-penetrating peptides (CPPs), current emphasis is on thiol-mediated uptake (TMU, TIMEUP) as the emerging method of choice to deliver any substrate of interest directly to the cytosol (proteins, oligonucleotides, nanoparticles, liposomes, polymersomes etc). TMU delivers into deep tissue and works in living animals, including genome editing. At the same time, dynamic-covalent inhibitors of TMU are of interest for drug discovery applications (antivirals, antithrombotics, antitumor).

By now, the power of TMU has been confirmed by many groups, but nobody knows how it really works. We think this is so because the underlying dynamic covalent cascade exchange chemistry is so very difficult. To decode the dynamic complex networks accounting for TMU, presumably, and identify the cellular exchange partners involved, we synthesize new cascade exchangers (CAXs, many), develop inclusive pattern generation protocols and bioconjugation methods, use modern proteomics approaches and cellular engineering, and grow dynamer materials by ring-opening polymerization.

Methods: These projects generate expertise in multistep synthesis and/or chemical biology, network analysis, polymer chemistry, membrane methods. Cellular uptake screening and network analysis benefit from state-of-the-art infrastructure and expertise in our ACCESS, Bioimaging Center, and CHEMBIO MS platforms: Cell culture, including spheroids, automated high-content high-throughput microscopic imaging, genetic engineering, overexpression, knockdown, co-localization, pulse-chase, proteomics, cell motility.

Collaborations: Internal bioimaging experts, occasional collaborations with biology groups to address specific delivery problems.

Recommended reading:

Saidjalolov, S.; Coelho, F.; Mercier, V.; Moreau, D.; Matile, S. “Inclusive Pattern Generation Protocols to Decode Thiol-Mediated Uptake,” ACS Cent. Sci. 2024, 10, 1033–1043.

Laurent, Q.; Martinent, R.; Lim, B.; Pham, A.-T.; Kato, T.; López-Andarias, J.; Sakai, N.; Matile, S. “Thiol-Mediated Uptake,” JACS Au 2021, 1, 710–728 (review).

Saidjalolov, S.; Chen, X.-X.; Moreno, J.; Cognet, M.; Wong-Dilworth, L.; Bottanelli, F.; Sakai, N.; Matile, S. “Asparagusic Golgi Trackers,” JACS Au, in press.

Bouffard, J.; Coelho, F.; Sakai, N.; Matile, S. “Dynamic Phosphorus: Thiolate Exchange Cascades with Higher Phosphorothioates,” Angew. Chem. Int. Ed. 2023, 62, e202313931.

Gasparini, G.; Bang, E.-K.; Molinard, G.; Tulumello, D. V.; Ward, S.; Kelley, S. O.; Roux, A.; Sakai, N.; Matile, S. “Cellular Uptake of Substrate-Initiated Cell-Penetrating Poly(disulfide)s,” J. Am. Chem. Soc. 2014, 136, 6069–6074.