Protein disulfide isomerase (PDI) can assist immature proteins to correctly fold by controlling cysteinyl disulfide (SS)‐relating reactions (i. e., SS‐formation, SS‐cleavage, and SS‐isomerization). PDI controls protein quality by suppressing protein aggregation, as well as functions as an oxidative folding catalyst. Following the amino acid sequence of the active center in PDI, basic amino acid conjugates of 1,2‐diselenan‐4‐amine (1), which show oxidoreductase‐ and isomerase‐like activities for SS‐relating reactions, were designed as a novel PDI model compound. By conjugating the amino acids, the diselenide reduction potential of compound 1 was significantly increased, causing improvement of the catalytic activities for all SS‐relating reactions. Furthermore, these compounds, especially histidine‐conjugated one, remarkably suppressed protein aggregation even at low concertation (0.3 mM∼). Thus, it was demonstrated that the conjugation of basic amino acids into 1 simultaneously achieves the enhancement of the redox reactivity and the capability to suppress protein aggregation.

Diselenide‐based S‐denitrosylase mimic: This study demonstrates the potential of 1,2‐diselenan‐4‐amine conjugated with Pro‐His dipeptide as a novel S‐denitrosylase mimic, which catalytically promotes cysteinyl S‐denitrosylation in the presence of a thiol co‐substrate and prevents protein misfolding caused by S‐nitrosylation. The cover image shows how the catalytic cycle involved a highly reactive diselenol species forming a γ‐turn structure, and highlights the mystique of the reaction controlled by Selene, goddess of the moon and origin of the name for the element, selenium. More information can be found in the Full Paper by K. Arai et al.

This study developed dipeptide‐conjugated 1,2‐diselenan‐4‐amine (1), i. e., 1‐Xaa‐His, as a new class of S‐denitrosylase mimic. The synthesized compounds, especially 1‐Pro‐His, remarkably promoted S‐denitrosylation of nitrosothiols (RSNO) via a catalytic cycle involving the reversible redox reaction between the diselenide and its corresponding diselenol ([SeH,SeH]) form with coexisting reductant thiols (R′SH), during which the [SeH,SeH] form as a key reactive species reduces RSNO to the corresponding thiol (RSH). Structural analyses of 1‐Pro‐His suggested that the peptide backbone of [SeH,SeH] is rigidly bent to form a γ‐turn, possibly including an NH⋅⋅⋅Se hydrogen bond between the imidazole ring of His and selenol group, thus stabilizing the [SeH,SeH] form thermodynamically, and dramatically enhancing the catalytic activity. Furthermore, the synthetic compounds were found to prohibit S‐nitrosylation‐induced protein misfolding in the presence of RSNO, eventually implying their potential as a drug seed for misfolding diseases caused by the dysregulation of the S‐denitrosylation system.

In a previous study, we reported that (S)-1,2-diselenane-4-amine (1) catalyzes oxidative protein folding through protein disulfide isomerase (PDI)-like catalytic mechanisms and that the direct conjugation of a basic amino acid (Xaa: His, Lys, or Arg) via an amide bond improves the catalytic activity of 1 by increasing its diselenide (Se–Se) reduction potential (E′°). In this study, to modulate the Se–Se redox properties and the association of the compounds with a protein substrate, new catalysts, in which a Gly spacer was inserted between 1 and Xaa, were synthesized. Exhaustive comparison of the PDI-like catalytic activities and E′° values among 1, 1-Xaa, and 1-Gly-Xaa showed that the insertion of a Gly spacer into 1-Xaa either did not change or slightly reduced the PDI-like activity and the E′° values. Importantly, however, only 1-Gly-Arg deviated from this generality and showed obviously increased E°′ value and PDI-like activity compared to the corresponding compound with no Gly spacer (1-Arg); on the contrary, its catalytic activity was the highest among the diselenide compounds employed in this study, while this abnormal enhancement of the catalytic activity of 1-Gly-Arg could not be fully explained by the thermodynamics of the Se–Se bond and its association ability with protein substrates.

Acceleration and suppression: Protein disulfide isomerase (PDI) controls protein quality by suppressing protein aggregation, as well as catalyzing oxidative protein folding in the cell. Basic amino acid conjugates of 1,2‐diselenan‐4‐amine, which were inspired by the unique chemical properties for the active center in PDI, effectively catalyze oxidative folding and refolding. In addition, the compounds also show a high suppressive ability against protein aggregation. The observed PDI‐like functions of the compounds suggest potential applications not only as an accelerator for protein folding but also as a medicine for misfolding diseases caused by insoluble misfolded proteins. More information can be found in the Full Paper by Kenta Arai et al.