Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been recently identified as a new useful target for hypercholesterolemia treatment. This work demonstrates that natural peptides, deriving from the hydrolysis of lupin protein and absorbable at intestinal level, are able to inhibit the proteinprotein interaction between PCSK9 and the low density lipoprotein receptor (LDLR). In order to sort out the best potential inhibitors among these peptides, a refined in silico model of the PCSK9/LDLR interaction was developed. Docking, molecular dynamics (MD) simulations and peptide binding energy estimations, by MM-GBSA approach, permitted to select the two best candidates among tested peptides that were synthesized and evaluated for their inhibitory activity. The most active was P5 that induced a concentration dependent inhibition of the PCSK9-LDLR binding, with an IC 50 value equal to 1.6 ± 0.33 μM. Tested at a 10 μM concentration, this peptide increased by 66 ± 21.4% the ability of HepG2 cells to take up LDL from the extracellular environment.An increased level of low-density lipoproteins (LDL) predisposes to the development of cardiovascular disease (CVD) and stroke. Currently, the main agents for lowering LDL levels are statins. They reduce the regulatory pool of intracellular cholesterol by competitively inhibiting HMGCoAR, the rate-limiting enzyme of endogenous cholesterol biosynthesis. This in turn activates the LDL receptor (LDLR) transcription, a process under the control of sterol regulatory element binding protein 2 (SREBP-2) 1,2 . The statin cholesterol-lowering action has been consistently shown to translate into fewer cardiovascular events [3][4][5] . Nevertheless, residual risk persists in a large portion of statin-treated individuals, owing to either inability to achieve desirable LDL levels 6,7 or presence of other traits predisposing to CVD 8,9 . Moreover, intolerance to statins produces numerous side effects, such as myopathy with a spectrum of consequences ranging from myalgia to rhabdomyolysis 10

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The seed of industrial hemp is an underexploited protein source. In view of a possible use in functional foods, a hempseed protein concentrate was hydrolyzed with pepsin, trypsin, pancreatin, or a mixture of these enzymes. A detailed peptidomic analysis using data-dependent acquisition showed that the numbers of peptides identified ranged from 90 belonging to 33 parent proteins in the peptic hydrolysate to 9 belonging to 6 proteins in the pancreatin digest. The peptic and tryptic hydrolysates resulted to be the most efficient inhibitors of 3-hydroxymethyl-coenzyme A reductase activity when tested on the catalytic domain of the enzyme. Using the open access tools PeptideRanker and BIOPEP, a list of potentially bioactive peptides was generated: the alleged activities included the antioxidant property, the glucose uptake stimulating activity, the inhibition of dipeptidyl peptidase-IV and angiotensin-converting enzyme I.