Vicinal thiol-containing signaling protein (VDP)

Vicinal thiol-containing signaling proteins are a functional class of proteins defined by the presence of two cysteine residues in close spatial proximity, often within a Cys-X-X-Cys or Cys-X-Cys motif [1]. These motifs are highly sensitive to redox changes and serve as critical regulatory sites where thiol-disulfide exchange can modulate protein function, stability, and signal transduction [2]. Key members of this group include thioredoxin (Trx), thioredoxin reductase (TrxR), protein disulfide isomerase (PDI), and the PML domain of the PML-RARα fusion protein [3][4]. Therapeutic agents like arsenic trioxide (ATO) target these proteins by forming stable, covalent cyclic dithioarsinite complexes with the vicinal thiols, which can lead to the functional inactivation or proteasomal degradation of the target [5]. This mechanism is most notably utilized in the treatment of acute promyelocytic leukemia (APL), where ATO-induced degradation of the PML-RARα oncoprotein triggers leukemic cell differentiation and apoptosis [6]. However, because vicinal thiols are widely distributed across the proteome, drugs targeting this motif often exhibit significant off-target effects, leading to safety concerns such as QT prolongation and hepatotoxicity [7].

Other names

Vicinal dithiol proteinsDithiol-containing proteinsRedox-sensitive signaling proteinsArsenic-binding proteins

Drugs targeting these proteins typically act through the covalent modification of vicinal thiol groups. For example, arsenic trioxide binds to closely spaced cysteine residues to form stable cyclic dithioarsinite structures, which induces conformational changes that lead to the inhibition of enzymatic activity or the degradation of the protein via the ubiquitin-proteasome pathway [1][5].