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The inhibition of the PCSK9/LDLR protein-protein interaction (PPI) is a promising strategy for developing new hypocholesterolemic agents. Recently, new antibodies have been approved for therapy, but the high cost and low patients’ compliance stimulate the development of alternatives. Starting from the structural information available for the complex between PCSK9 and TVFTSWEEYLDWV (Pep2-8) peptide inhibitor and using computational methods, in this work we identified two Pep2-8 analogs as potential inhibitors of the PCSK9/LDLR PPI. Their biological characterization confirmed the theoretical outcomes. Remarkably, the treatment of HepG2 cells with these peptides increased the LDLR protein level on the cellular membrane, with activities that were 100 and 50 times better than the one of Pep2-8 tested at a 50 μM concentration. Moreover, they were 50 and 5 times more active than Pep2-8 in improving the functional ability of HepG2 cells to uptake extracellular LDL.

Biological Characterization of Computationally Designed Analogs of peptide TVFTSWEEYLDWV (Pep2-8) with Increased PCSK9 Antagonistic Activity