The inhibition of the PCSK9/LDLR protein-protein interaction is a promising strategy for developing new hypocholesterolemic agents. Familial hypercholesterolemia is linked to specific PCSK9 mutations: the D374Y is the most potent gain-of-function (GOF) PCSK9 mutation among clinically relevant ones. Recently, a lupin peptide (T9) showed inhibitory effects on this mutant PCSK9 form, being also capable to increase liver uptake of low density lipoprotein cholesterol. In this Letter, aiming to improve the potency of this peptide, the T9 residues mainly responsible for the interaction with PCSK9D374Y (hot spots) were computationally predicted. Then, the "non-hot" residues were suitably substituted by new amino acids capable to theoretically increase the structural complementarity between T9 and PCSK9D374Y. The outcomes of this study were confirmed by in vitro biochemical assays and cellular investigations, showing that a new T9 analog is able to increase the LDLR expression on the liver cell surface by 84% at the concentration of 10 μM.