Selenium-Centered Cascade Exchangers and Conformational Control Unlock Unique Patterns of Thiol-Mediated Cellular Uptake

Dynamic-covalent electrophiles called cascade exchangers (CAXs) can reversibly engage cell-surface thiols. Conjugates between CAXs and molecular or even protein-sized cargos can deliver these cargos into cells by thiol-mediated uptake (TMU); free CAXs can also hinder TMU presumably by competing for thiol exchange sites. So far, three orthogonal networks of cellular thiol exchange partners have been identified to participate in TMU, centering on the transferrin receptor, integrins, and protein disulfide isomerases. This study introduces cyclic selenenylsulfides as a new CAX type, with polarised reactivity that brings important differences from the known disulfide and diselenide CAXs. Additionally, this study introduces methods to modulate CAX activity by employing remote functional groups to tune ring re-closure rates, e. g. via thiolate de/stabilization by hydrogen bonding and ion pairing. Differently to all CAXs known, Se-centred CAXs participate in two different TMU networks (integrins preferred, PDIA3 tolerated). When free, the remotely tuned Se-centred CAXs were strong inhibitors of most TMU systems, but again brought a novel feature: they increased the uptake of tetrel-centred Michael acceptor CAXs, making them the first free CAX we know of that can accelerate TMU. We conclude that Se- and tetrel-centred CAXs share a cellular thiol exchange partner that hinders TMU, which may be a target for improving the delivery of Michael acceptor drugs. The unique thiol exchange partner patterns generated by Se-centered CAXs with remotely tuned ring closure motifs support that they will prove a valuable tool to help decode TMU and achieve chemical control over cellular entry on the molecular level.