Design and Synthesis of Senescence-Targeted Prodrugs with Senomorphic and Senolytic Properties To Mitigate...

Area of Science:

• Biomedical Science
• Pharmacology
• Nephrology

Background:

• Chemotherapy can cause kidney injury due to cellular senescence, a complex process where early-stage senescent cells aid repair.
• Senotherapeutics, including senolytics and senomorphics, aim to manage senescence-related damage.
• Existing senotherapeutics face challenges due to the dual role of senescent cells.

Purpose of the Study:

• To repurpose bardoxolone methyl (CDDOMe) into a senomorphic agent for chemotherapy-induced kidney injury.
• To design and synthesize novel senescence-associated β-galactosidase (SA-β-gal) activated prodrugs.
• To evaluate the efficacy of the optimal prodrug, Gal-CDD-01, in mitigating kidney injury.

Main Methods:

• Bardoxolone methyl (CDDOMe) was modified into SA-β-gal activated prodrugs.
• The optimal prodrug, Gal-CDD-01, was identified and characterized.
• In vivo studies were conducted in mice with chemotherapy-induced kidney injury to assess Gal-CDD-01's efficacy and distribution.

Main Results:

• Gal-CDD-01 selectively induced apoptosis in late-stage senescent cells.
• Gal-CDD-01 suppressed the progression of early-stage senescent cells.
• In vivo administration of Gal-CDD-01 showed favorable efficacy and distribution, improving motor function in mice with kidney injury.

Conclusions:

• Gal-CDD-01 represents a dual-functional, senescence-targeted prodrug.
• This novel agent effectively mitigates chemotherapy-induced kidney injury.
• Gal-CDD-01 shows promise for therapeutic applications in kidney damage repair.