Potent Inducers of Paraptosis through Electronic Tuning of Hemicyanine Electrophiles

Paraptosis is a distinct form of programmed cell death characterized by cytoplasmic vacuolization, mitochondrial swelling, and endoplasmic reticulum (ER) dilation, offering an alternative to apoptosis for therapeutic applications. In this study, we identified a hemicyanine derivative that is a potent paraptosis inducer in two cancer cell lines. This compound triggers hallmark paraptotic features, including ER swelling, mitochondrial morphological changes, increased superoxide production, and caspase-independent cell death. This activity is dependent on the ability of the probe to modify thiols covalently. Proteomic analysis using a biotinylated, activity-based probe revealed Sec23 homologue A and GDP-dissociation inhibitor alpha as potential targets implicated in paraptosis activation. This lead compound already displayed some degree of selectivity, exemplified by its minimal interaction with well-known nucleophilic protein targets such as protein disulfide isomerases. These findings establish the hemicyanine chemical family as a promising scaffold for paraptosis research and suggest potential as a therapeutic lead for diseases where traditional apoptosis pathways are dysregulated.