title: Lupin Peptides Modulate the Protein-Protein Interaction of PCSK9 with the Low Density Lipoprotein Receptor in HepG2 Cells.
abstract: 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 protein-protein 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 IC50 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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Milan, Milan, Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: Lammi
authors.affiliation: Department of Pharmaceutical Sciences, University of Milan, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Zanoni
authors.affiliation: Department of Pharmaceutical Sciences, University of Milan, Milan, Italy.
authors.forename: Gilda
authors.initials: G
authors.lastname: Aiello
authors.affiliation: Department of Pharmaceutical Sciences, University of Milan, Milan, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Arnoldi
authors.affiliation: Department of Pharmaceutical Sciences, University of Milan, Milan, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Grazioso
mesh_terms: D000595:Amino Acid Sequence; D018938:Caco-2 Cells; D005453:Fluorescence; D006801:Humans; D031297:Lupinus / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D010940:Plant Proteins / Q000737:chemistry / Q000494:pharmacology*; D000071449:Proprotein Convertase 9 / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011973:Receptors, LDL / Q000737:chemistry / Q000378:metabolism*
chemical_list: C573412:LDLR protein, human; D010455:Peptides; D010940:Plant Proteins; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9