Title: TRANSLATIONAL SUPRAMOLECULAR CHEMISTRY: NEW TOOLS TO IMAGE AND CROSS MEMBRANES

Time: 

2024-04-29 10:30

Lecturer:  Professor Stefan Matile

University of Geneva

Venue: Room 202, Lecture Hall, Lu-Jiaxi Building, Siming Campus

Abstract：

Central current challenges at the chemical biology interface include the control over the entry into cells and the fluorescence imaging of physical forces in living systems.

To penetrate cells, we have systematically developed thiol-mediated uptake (TMU, TIMEUP) as a promising alternative to cell-penetrating peptides.  It becomes increasingly clear TMU operates with encoded networks of dynamic covalent exchange cascades to generally bring matter into cells, reminiscent of molecular walkers.  Their complexity is probably the reason why TMU is not better known and understood.  The cytosolic delivery of otherwise elusive substrates of interest (SOI), from quantum dots or genome editing tools, is unproblematic with TMU, also in deep tissue.  TMU explains the cell-penetrating nature of antisense oligonucleotide phosphorothioates, works in living animals, and can inhibit the entry of pathogens.  Proteomics and emerging pattern generation protocols assign the transferrin receptor, protein disulfide isomerases and integrins as exchange partners in orthogonal networks.  The latter confirm that TMU is interesting not only for drug delivery but also for drug discovery, expanding potential from antivirals toward the inhibition of thrombosis and tumor progression.

For mechanobiology imaging with small-molecules probes, fluorescent flippers have been designed (first in 2012), synthesized, evaluated, validated and commercialized (first in 2018).  They are small molecule probes that respond to membrane tension.  Fluorescent flippers operate as twisted push-pull probes that report changes in membrane tension as physical de/compression in equilibrium in the ground state.  The result are giant shifts of excitation maxima and fluorescence lifetimes.  The latter are important for bioimaging by FLIM.  In biomembranes, increasing lifetimes with increasing tension indicate that flippers report on membrane reorganization, particularly tension-induced microdomain dis/assembly.  Flippers have been developed to target essentially any membrane of interest (MOI), either by empirical tracking or by genetic engineering (HaloFlippers, RUSH).  Realized examples include plasma membranes (including asymmetry), mitochondria (fission), endocytosis, secretory pathway with ER, Golgi, nuclear envelope, and release by chemical stimulation or with light.  Expansion of flipper design covers blinking for superresolution, dual sensing by dynamic covalent hydration, and the sensing of unusually thick membrane domains within cells.

Stefan Matile is a Full Professor in the Department of Organic Chemistry at the University of Geneva, a founding member of the National Centre of Competence in Research (NCCR) Chemical Biology and a founding member of the NCCR Molecular Systems Engineering. He currently holds a CH-ERC Advanced Grant (2022) and an SNSF Excellence Grant (2021, by invitation), his first ERC AdG he received in 2010.  He is the co-author of more than 370 publications, many in top society-based journals (67 JACS/Au, etc), and has delivered over 300 lectures all over the world.  His research interests are centered around translational supramolecular chemistry, supramolecular systems (th)at work, at the interface of synthetic organic chemistry, chemical biology and materials chemistry, expecting that offering molecules new ways to get in touch will provide access to new structures and functions which ultimately will allow us to approach the big questions from new directions.  Recent highlights are the discovery of catalysis with anion-π interactions, with chalcogen and pnictogen bonds, and in electric fields in microfluidic devices, of mechanosensitive probes to image physical forces in biology (fluorescent flippers, commercialized), and of dynamic covalent exchange cascades to enter into cells and hinder viruses to do the same.  Educated at the University of Zurich (PhD, with Wolf Woggon) and Columbia University in New York (postdoc, with Koji Nakanishi), he started his independent academic career as an Assistant Professor at Georgetown University, Washington DC, before moving to Geneva.