Dithiolane quartets: thiol-mediated uptake enables cytosolic delivery in deep tissue

Article Article scientifique Article Dithiolane quartets: thiol-mediated uptake enables cytosolic delivery in deep tissue eng 2021-10-06 2021-11-07 author Martinent Rémi 885155 author Tawffik Salman 840554 author Lopez Andarias Javier 810949 author Moreau Dimitri 0000-0002-9282-3324 751508 author Laurent Quentin François Antoine 893791 author Matile Stefan 0000-0002-8537-8349 129654 13922-13929 10.1039/D1SC04828G 2041-6520 http://xlink.rsc.org/?DOI=D1SC04828G The cytosolic delivery of various substrates in 3D multicellular spheroids by thiol-mediated uptake is reported. This is important because most orthodox systems, including polycationic cell-penetrating peptides, fail to deliver efficiently into deep tissue. The grand principles of supramolecular chemistry, that is the pH dependence of dynamic covalent disulfide exchange with known thiols on the transferrin receptor, are proposed to account for transcytosis into deep tissue, while the known but elusive exchange cascades along the same or other partners assure cytosolic delivery in kinetic competition. For quantitative detection in the cytosol, the 2D chloroalkane penetration assay (CAPA) is translated to 3D deep tissue. The targeted delivery of quantum dots, otherwise already troublesome in 2D culture, and the controlled release of mechanophores are realized to exemplify the power of thiol-mediated uptake into spheroids. As transporters, dithiolane quartets on streptavidin templates are introduced as modular motifs. Built from two amino acids only, the varied stereochemistry and peptide sequence are shown to cover maximal functional space with minimal structural change, i.e., constitutional isomers. Reviving a classic in peptide chemistry, this templated assembly of β quartets promises to expand streptavidin biotechnology in new directions, while the discovery of general cytosolic delivery in deep tissue as an intrinsic advantage further enhances the significance and usefulness of thiol-mediated uptake. Dewey 540 36 Département de chimie organique 141 39 Département de biochimie 144 false 761 Groupe Matile Chemical science 12 41 87dc02b5-673a-4a2b-897a-686e78d93a82 Article (Published version) Public Article-scientifique-from-unpaywall.pdf 2036115 application/pdf CC BY Vignette Public Get.gif 31572 image/gif openAccess Faculté des sciences / Section de chimie et biochimie / Département de chimie organique Faculté des sciences / Section de chimie et biochimie / Département de biochimie

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Dithiolane quartets: thiol-mediated uptake enables cytosolic delivery in deep tissue	Chemical science			2021	266	189

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Tawffik, Salman