Thiol-reactive inhibitors for the cellular entry of cyclic oligochalcogenide (COC) transporters and SARS-CoV-2 spike pseudo-lentivirus are reported.

Thiol‐mediated uptake is emerging as method of choice to penetrate cells. This study focuses on irreversible covalent inhibitors of thiol‐mediated uptake. High‐content high‐throughput screening of the so far largest collection of hypervalent iodine reagents affords inhibitors that are more than 250 times more active than Ellman’s reagent and rival the best dynamic covalent inhibitors. Comparison with other irreversible reagents reveals that inhibition within one series follows reactivity, whereas inhibition across series deviates from reactivity. These trends support that molecular recognition, besides dynamic covalent exchange, contributes significantly to thiol‐mediated uptake. The most powerful inhibitors besides the best hypervalent iodine reagents were Fukuyama’s nosyl protecting group and super‐cinnamaldehydes that have been introduced as irreversible activators of the pain receptor TRPA1. Considering that several viruses use different forms of thiol‐mediated uptake to enter cells, the identification of new irreversible inhibitors of thiol‐mediated uptake is of general interest for the discovery of new antivirals.

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We report design, synthesis and evaluation of a series of naphthalenediimides (NDIs) that are bridged with short peptides. Reminiscent of peptide stapling technologies, the macrocycles are conveniently accessible by a chromogenic nucleophilic aromatic substitution of two bromides in the NDI core with two thiols from cysteine sidechains. The dimension of core-bridged NDIs matches that of one turn of an α helix. NDI-stapled peptides exist as two, often separable atropisomers. Introduction of tertiary amine bases in amino-acid sidechains above the π-acidic NDI surface affords operational anion-π catalysts. According to an enolate chemistry benchmark reaction, anion-π catalysis next to peptides occurs with record chemoselectivity but weak enantioselectivity. Catalytic activity drops with increasing distance of the amine base to the NDI surface, looser homocysteine bridges, mismatched, shortened and elongated α-helix turns, and acyclic peptide controls. Elongation of isolated turns into short α helices significantly increases activity. This increase is consistent with remote control of anion-π catalysis from the α-helix macrodipole.