Senolysis Enabled by Senescent Cell-Sensitive Bioorthogonal Tetrazine Ligation

Area of Science:

• Biochemistry
• Cell Biology
• Drug Discovery

Background:

• Senescent cell clearance shows potential in slowing aging and enhancing cancer chemotherapy.
• Developing effective senolytics remains a significant challenge in therapeutic research.

Purpose of the Study:

• To establish a senolytic strategy using senescent cell-sensitive bioorthogonal tetrazine ligation.
• To demonstrate the selective detection and elimination of senescent cells.
• To explore the application of this strategy for targeted delivery of proteolysis-targeting chimeras (PROTACs) as senolytics.

Main Methods:

• A dihydrotetrazine (Tz) linked to galactose (Gal) moiety (Gal-Tz) was designed to recognize senescence-associated β-galactosidase.
• Gal-Tz facilitated the click-release of a fluorescent probe and doxorubicin from a caged prodrug.
• The strategy was adapted for selective activation and delivery of PROTAC prodrug TCO-ARV-771 to induce degradation of bromodomain-containing protein 4.

Main Results:

• The Gal-Tz system achieved efficient detection and elimination of senescent HeLa and A549 cells with a senolytic index of 16.44.
• Selective activation and delivery of PROTACs into senescent cells were successfully demonstrated.
• The approach showed selective induction of bromodomain-containing protein 4 degradation in senescent cells.

Conclusions:

• Bioorthogonal tetrazine ligation is a viable strategy for the selective removal of senescent cells.
• This approach offers a promising method for targeted senolytic therapy, including the use of PROTACs.
• The findings pave the way for new interventions targeting cellular senescence in aging and disease.