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

Abstract

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.

Dynamic Covalent Michael Acceptors to Penetrate Cells: Thiol‐Mediated Uptake with Tetrel‐Centered Exchange Cascades, Assisted by Halogen‐Bonding Switches

“…Thiol‐mediated uptake (TMU) refers to cell penetration of dynamic covalent cascade exchangers (CAXs) that can be inhibited by thiol‐reactive agents (Figure 1A) [1, 2] . TMU excels in cytosolic delivery in deep tissue, [3] and inhibitors are promising with regard to drug discovery, particularly as antivirals [4–7] . So far, the focus has been almost exclusively on chalcogen‐centered CAXs, particularly cyclic or polymeric disulfides, e.g., 1 (Figure 1B) [1, 6] .…”

“…So far, the focus has been almost exclusively on chalcogen‐centered CAXs, particularly cyclic or polymeric disulfides, e.g., 1 (Figure 1B) [1, 6] . Recently, pnictogen‐centered CAXs have been introduced, including bismuth complex 2 , a powerful inhibitor of lentivirus entry [7] . Here, we introduce tetrel‐centered CAXs to TMU.…”

“…[1,2] TMU excels in cytosolic delivery in deep tissue, [3] and inhibitors are promising with regard to drug discovery, particularly as antivirals. [4][5][6][7] So far, the focus has been almost exclusively on chalcogen-centered CAXs, particularly cyclic or polymeric disulfides, e.g., 1 (Figure 1B). [1,6] Recently, pnictogencentered CAXs have been introduced, including bismuth complex 2, a powerful inhibitor of lentivirus entry.…”

Dynamic Covalent Michael Acceptors to Penetrate Cells: Thiol‐Mediated Uptake with Tetrel‐Centered Exchange Cascades, Assisted by Halogen‐Bonding Switches

“…[ 1 , 2 ] TMU excels in cytosolic delivery in deep tissue, [3] and inhibitors are promising with regard to drug discovery, particularly as antivirals. [ 4 , 5 , 6 , 7 ] So far, the focus has been almost exclusively on chalcogen‐centered CAXs, particularly cyclic or polymeric disulfides, e.g., 1 (Figure 1 B). [ 1 , 6 ] Recently, pnictogen‐centered CAXs have been introduced, including bismuth complex 2 , a powerful inhibitor of lentivirus entry.…”

“…[ 1 , 6 ] Recently, pnictogen‐centered CAXs have been introduced, including bismuth complex 2 , a powerful inhibitor of lentivirus entry. [7] Here, we introduce tetrel‐centered CAXs to TMU.…”