Computational Design, Synthesis, and Biological Evaluation of Diimidazole Analogues Endowed with Dual PCSK9/HMG-CoAR-Inhibiting Activity

Proprotein convertase subtilisin/kexin 9 (PCSK9) is responsiblefor 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 treatmentof hypercholesterolemia and cardiovascular diseases. In our studies,we discovered Rim13, a polyimidazole derivative reducingthe protein-protein interaction between PCSK9 and LDLR withan IC50 of 1.6 mu M. The computational design ledto 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-loweringactivity of the new analogues and using both biochemical and cellulartechniques, compound Dim16 displayed improved PCSK9 inhibitoryactivity (IC50 0.9 nM). Interestingly, similar to otherlupin-derived peptides and their synthetic analogues, some compoundsin this series showed dual hypocholesterolemic activity since someof them complementarily inhibited the 3-hydroxy-3-methylglutaryl coenzymeA reductase.