Proprotein convertase subtilisin/kexin 9 (PCSK9) is responsible
for the degradation of the hepatic low-density lipoprotein receptor
(LDLR), which regulates circulating cholesterol levels. Consequently,
the PCSK9 inhibition is a valuable therapeutic approach for the treatment
of hypercholesterolemia and cardiovascular diseases. In our studies,
we discoveredRim13, a polyimidazole derivative reducing
the protein–protein interaction between PCSK9 and LDLR with
an IC50of 1.6 μM. The computational design led
to the optimization of the shape of the PCSK9/ligand complementarity,
enabling the discovery of potent diimidazole derivatives. In fact,
carrying out biological assays to fully characterize the cholesterol-lowering
activity of the new analogues and using both biochemical and cellular
techniques, compoundDim16displayed improved PCSK9 inhibitory
activity (IC500.9 nM). Interestingly, similar to other
lupin-derived peptides and their synthetic analogues, some compounds
in this series showed dual hypocholesterolemic activity since some
of them complementarily inhibited the 3-hydroxy-3-methylglutaryl coenzyme
A reductase.