Proprotein convertase subtilisin/kexin type 9 (PCSK9) is involved in cholesterol homeostasis, because it induces the low-density lipoprotein receptor (LDLR) degradation. This protein may carry some positive or negative mutations: PCSK9D374Y is one of the most dangerous gain-of-function mutations. This paper reports the identification of the first food-derived peptide able to inhibit the protein-protein interaction (PPI) between PCSK9D374Y and LDLR. In fact, T9 (GQEQSHQDEGVIVR), an absorbable peptide deriving from lupin β-conglutin, is able to impair the PPI between PCSK9D374Y and the LDLR, with an IC50 value equal to 285.6 ± 2.46 μM. The consequence of this inhibition is an increase of the protein level of the LDLR located on hepatic cell membranes up to 74.3 ± 4.4% and the restoration of the functional capability of HepG2 cells to uptake extracellular low-density lipoprotein up to 83.1 ± 1.6%. Finally, the putative binding mode of T9 to the LDLR binding site located on PCSK9D374Y was postulated by in silico tools.
Keywords: HepG2 cells; LDLR; PCSK9 inhibitors; bioactive peptides; functional foods.