Multidisciplinary strategy to investigate new lupin peptide inhibitors of PCSK9 activity as useful approach for cardiovascular disease risk reduction

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been recently identified as a new target for hypercholesterolemia treatment. The main role exploited by PCSK9 is the degradation of LDL receptor (LDLR) protein, leading to an increase of plasma cholesterol level. In this context, inhibition of PCSK9 is considered a good strategy for the treatment of hypercholesterolemia [1]. Recently, our research was focused mainly on lupin peptides, since in a recent paper it was shown that in hypercholesterolemic subjects, who had consumed dietary bars containing lupin protein for a month, the total cholesterol decrease was accompanied by a parallel decrement of circulating PCSK9 (-8.5%) versus the control group that had consumed casein bars [2]. For this reason, a multidisciplinary investigation was carried out in order to screen and develop new peptides, deriving from lupin protein hydrolysis and absorbable at intestinal level, which are able to modulate the PCSK9 target with a dual mechanism of action. More in details, lupin peptides reduce PCSK9 production and secretion through a decrease of HNF1-alpha in HepG2 cells and an absorbed lupin peptide, LILPKHSDAD (P5), is able to inhibit the protein-protein interaction (PPI) between PCSK9 and the LDLR with an IC50 value equal to 1.6±0.33 μM. In this context, a molecular docking analysis has allowed us to simulate the effects induced by P5 on the binding of PCSK9 to the LDLR (Figure 1. Simulation of the inhibitory binding of PCSK9 induced by P5). In fact, the superimposition of P5 on the EGF-A domain of LDLR co-crystallized with PCSK9 (PDB code 4NE9) showed a good overlapping, justifying the P5 inhibitory property.