| Autor: |
Lammi C; Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milan, Italy., Fassi EMA; Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milan, Italy., Manenti M; Dipartimento di Chimica, Università degli Studi di Milano, Via Golgi 10, 20133 Milan, Italy., Brambilla M; Centro Cardiologico Monzino IRCCS, via Parea 4, 20138 Milan, Italy., Conti M; Centro Cardiologico Monzino IRCCS, via Parea 4, 20138 Milan, Italy., Li J; Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milan, Italy., Roda G; Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milan, Italy., Camera M; Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milan, Italy.; Centro Cardiologico Monzino IRCCS, via Parea 4, 20138 Milan, Italy., Silvani A; Dipartimento di Chimica, Università degli Studi di Milano, Via Golgi 10, 20133 Milan, Italy., Grazioso G; Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milan, Italy. |
| Abstrakt: |
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 discovered Rim13 , a polyimidazole derivative reducing the protein-protein interaction between PCSK9 and LDLR with an IC 50 of 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, compound Dim16 displayed improved PCSK9 inhibitory activity (IC 50 0.9 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. |
