Pnictogen-Centered Cascade Exchangers for Thiol-Mediated Uptake: As(III)‑, Sb(III)‑, and Bi(III)-Expanded Cyclic Disulfides as Inhibitors of Cytosolic Delivery and Viral Entry

Dynamic covalent
exchange cascades with cellular thiols are of
interest to deliver substrates to the cytosol and to inhibit the entry
of viruses. The best transporters and inhibitors known today are cyclic
cascade exchangers (CAXs), producing a new exchanger with every exchange,
mostly cyclic oligochalcogenides, particularly disulfides. The objective
of this study was to expand the dynamic covalent chalcogen exchange
cascades in thiol-mediated uptake by inserting pnictogen relays. A
family of pnictogen-expanded cyclic disulfides covering As­(III), Sb­(III),
and Bi­(III) is introduced. Their ability to inhibit thiol-mediated
cytosolic delivery is explored with fluorescently labeled CAXs as
transporters. The promise of inhibiting viral entry is assessed with
SARS-CoV-2 lentiviral vectors. Oxygen-bridged seven-membered 1,3,2-dithiabismepane
rings are identified as privileged scaffolds. The same holds for six-membered
1,3,2-dithiarsinane rings made from asparagusic acid and para-aminophenylarsine oxide, which are inactive or toxic when used alone.
These chemically complementary Bi­(III) and As­(III) cascade exchangers
inhibit both thiol-mediated cytosolic delivery and SARS-CoV-2 lentivector
uptake at concentrations of 10 μM or lower. Crystal structures,
computational models, and exchange kinetics support that lentivector
entry inhibition of the contracted dithiarsinane and the expanded
dithiabismepane rings coincides with exchange cascades that occur
without the release of the pnictogen relay and benefit from noncovalent
pnictogen bonds. The identified leads open perspectives regarding
drug delivery as well as unorthodox approaches toward dynamic covalent
inhibition of cellular entry.