期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 63, 期 24, 页码 16028-16042出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c01913
关键词
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资金
- National Key R&D Program of China [2019YFA0802701]
- Natural Science Foundation of China (NSFC) [91957114, 31671195, 31971066, 32021003]
- Front Youth Academic Team Program of HUST
- Integrated Innovative Team for Major Human Diseases Program of Tongji Medical College, HUST
Acute kidney injury (AKI), mostly caused by renal ischemia-reperfusion (I/R) injury and nephrotoxins, is characterized by rapid deterioration in renal-functions without effective drug treatment available. Through activation of a G protein-coupled receptor APJ, a furin-cleaved fragment of Elabela (ELA[22-32], E11), an endogenous APJ ligand, protects against renal I/R injury. However, the poor plasma stability and relatively weak APJ-binding ability of E11 limit its application. To address these issues, we rationally designed and synthesized a set of E11 analogues modified by palmitic acid (Pal) or polyethylene glycol; improved plasma stability and APJ-binding capacity of these analogues were achieved. In cultured renal tubular cells, these analogues protected against hypoxia-reperfusion or cisplatin-caused injury. For renal I/R-injured mice, these analogues showed improved reno-protective effects than E11; notably, Pal-E11 showed therapeutic effects at 24 h post I/R injury. These results present ELA analogues as potential therapeutic options in managing AKI.
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