期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 24, 期 17, 页码 -出版社
MDPI
DOI: 10.3390/ijms241713127
关键词
RNA-binding protein; human antigen R (HuR); high-throughput virtual screening; small molecule inhibitors; RNA pulldown assay
In this study, novel HuR inhibitors were identified using a combination of chemoinformatic methods, high-throughput virtual screening, and RNA-protein pulldown assays. The 4-(2-(2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene)hydrazineyl)benzoate ligand showed dose-dependent inhibition of HuR binding. This novel chemical scaffold provides a new avenue for the design of pharmaceutical agents targeting HuR.
The RNA-binding protein human antigen R (HuR) regulates stability, translation, and nucleus-to-cytoplasm shuttling of its target mRNAs. This protein has been progressively recognized as a relevant therapeutic target for several pathologies, like cancer, neurodegeneration, as well as inflammation. Inhibitors of mRNA binding to HuR might thus be beneficial against a variety of diseases. Here, we present the rational identification of structurally novel HuR inhibitors. In particular, by combining chemoinformatic approaches, high-throughput virtual screening, and RNA-protein pulldown assays, we demonstrate that the 4-(2-(2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene)hydrazineyl)benzoate ligand exhibits a dose-dependent HuR inhibition effect in binding experiments. Importantly, the chemical scaffold is new with respect to the currently known HuR inhibitors, opening up a new avenue for the design of pharmaceutical agents targeting this important protein.
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