First Food-Derived Peptide Inhibitor of the Protein-Protein Interaction between Gain-of-Function PCSK9D374Y and the Low-Density Lipoprotein Receptor

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: PCSK9(D374Y) 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 PCSK9(D374Y) and LDLR In fact, T9 (GQEQSHQDEGVIVR), an absorbable peptide deriving from lupin beta-conglutin, is able to impair the PPI between PCSK9(D374Y) and the LDLR, with an IC50 value equal to 285.6 +/- 2.46 mu M. 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 PCSK9(D374Y) was postulated by in silico tools.