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.
Lupin peptides modulate the protein-protein interaction of PCSK9 with the low density lipoprotein receptor in HepG2 cells / C. Lammi, C. Zanoni, G. Aiello, A. Arnoldi, G. Grazioso. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 6(2016 Jul 18), pp. 29931.1-29931.13.
|Titolo:||Lupin peptides modulate the protein-protein interaction of PCSK9 with the low density lipoprotein receptor in HepG2 cells|
LAMMI, CARMEN (Primo)
ZANONI, CHIARA (Secondo)
ARNOLDI, ANNA (Corresponding)
GRAZIOSO, GIOVANNI (Ultimo)
|Parole Chiave:||C-terminal domain; molecular-mechanics; LDL receptors; proprotein convertases; docking performance; crystal-structures; flexible docking; scoring function; web server; binding|
|Settore Scientifico Disciplinare:||Settore CHIM/08 - Chimica Farmaceutica|
Settore CHIM/10 - Chimica degli Alimenti
|Data di pubblicazione:||18-lug-2016|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1038/srep29931|
|Appare nelle tipologie:||01 - Articolo su periodico|