靶向降解肾损伤分子1改善急性肾损伤的PROTAC策略研究

Abstract

Acute kidney injury (AKI) is a global public health issue with a high incidence and mortality rate, without effective treatments currently available. Kidney injury molecule 1 (KIM1), an FDA-approved biomarker for AKI, is dramatically induced on the membrane of injured renal tubular epithelial cells. However, whether it works as a therapeutic target remains unclear. Herein, by using a modified Proteolysis Targeting Chimera (PROTAC) strategy, we constructed KIM1-targeted degradable liposome (KIM1-TDL) by conjugating a KIM1-targeting peptide TKP4 that we previously designed, and an E3 ligase ligand lenalidomide to lipid linkers, which were subsequently used to co-modify liposome surfaces. In cisplatin-induced cellular and mouse AKI models, KIM1-TDL bound to KIM1 and was then internalized. Through degradation by the ubiquitin-proteasome system, KIM1-TDL reduced injury-caused elevation of KIM1 levels, and alleviated the AKI. Together, our results indicate KIM1 as a potential therapeutic target for AKI, and provide a simplified approach to achieve targeted KIM1 degradation.