AIM: The discovery of PCSK9 as a key modulator in cholesterol homeostasis led to the development of several strategies to inhibit its activity in hypercholesterolemic patients. To this aim, monoclonal antibodies, small interfering RNA and vaccines have been developed for targeting PCSK9. Objective of this study has been the in vitro investigation of small molecules with PCSK9 inhibitory activity. METHODS: The effect of four small chemical entities on PCSK9 expression were assessed by using HepG2 cell line by the means of RT-qPCR, ELISA, Western Blot, Luciferase Promoter Activity and LDL-cholesterol uptake assays. RESULTS: One of the compounds, MR-39, strongly inhibited PCSK9 mRNA levels in a concentration-dependent manner (-46% at 6.25µM, the lowest concentration tested) and the protein expression at both intracellular (-70%) and extracellular (-30%) levels. MR-39 increased both SREBP2 and HNF1α protein, two transcriptional factors involved in the regulation of PCSK9. However, no effect was observed by MR-39 on PCSK9 promoter activity and did not significantly improve the LDL-cholesterol uptake by HepG2 cells. Interestingly, MR39 counteracted the transcriptional induction of PCSK9 by simvastatin and significantly improved the LDL-uptake of simvastatin (+30% and +75% at 6.25µM and 12.5µM of MR39, respectively). Similar results were observed for all four small chemical entities, suggesting similar basic molecular mechanism of action. CONCLUSIONS: MR small molecules can be considered as starting point for developing new innovative inhibitors of PCSK9 to be utilized in combination with simvastatin.
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