S-Denitrosylase-Like Activity of Cyclic Diselenides Conjugated with Xaa-His Dipeptide: Role of Proline Spacer as a Key Activity Booster

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.