Computationally Driven Structure Optimization, Synthesis, and Biological Evaluation of Imidazole-Based Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Inhibitors.
- Lammi C Dipartimento di Scienze Farmaceutiche , Universitá degli Studi di Milano , Via L. Mangiagalli 25 , 20133 Milan , Italy.
- Sgrignani J Istituto di Ricerca in Biomedicina (IRB) , Universitá della Svizzera Italiana (USI) , Via V. Vela 6 , CH-6500 Bellinzona , Switzerland.
- Arnoldi A Dipartimento di Scienze Farmaceutiche , Universitá degli Studi di Milano , Via L. Mangiagalli 25 , 20133 Milan , Italy.
- Lesma G Dipartimento di Chimica , Universitá degli Studi di Milano , Via Golgi 19 , 20133 Milan , Italy.
- Spatti C Dipartimento di Chimica , Universitá degli Studi di Milano , Via Golgi 19 , 20133 Milan , Italy.
- Silvani A Dipartimento di Chimica , Universitá degli Studi di Milano , Via Golgi 19 , 20133 Milan , Italy.
- Grazioso G Dipartimento di Scienze Farmaceutiche , Universitá degli Studi di Milano , Via L. Mangiagalli 25 , 20133 Milan , Italy.
- 2019-07-02
Published in:
- Journal of medicinal chemistry. - 2019
Drug Design
Hep G2 Cells
Humans
Imidazoles
Lipoproteins, LDL
Molecular Dynamics Simulation
Peptidomimetics
Proprotein Convertase 9
Protease Inhibitors
Protein Binding
Receptors, LDL
English
Proprotein convertase subtilisin/kexin 9 (PCSK9) is responsible for the degradation of the hepatic low-density lipoprotein receptor (LDLR), which in turn regulates the circulating low-density lipoprotein cholesterol (LDL-C) level. For this reason, the PCSK9 inhibition, by small molecules or peptides, is a validated therapeutic approach for fighting hypercholesterolemia and cardiovascular diseases. In this field, we have recently reported an imidazole-based peptidomimetic that has shown PCSK9 inhibitory activity in the micromolar range. Here, by applying advanced computational techniques, the binding mechanism of that imidazole peptidomimetic was predicted. Then, among a small set of poly-imidazole analogs, compounds showing the highest theoretical affinity were suitably synthesized, relying on a van Leusen reaction based multicomponent strategy. One compound (named RIm13) displayed a PCSK9 inhibitory activity 10-fold lower than the template compound, and, remarkably, at a concentration of 1 μM, it successfully prevented the LDLR degradation mediated by PCSK9 on HepG2 cells. As well as increasing the LDL uptake at the same concentration, RIm13 represents currently one of the most potent small molecules targeting the PCSK9/LDLR protein-protein interaction.
- Language
-
- English
- Open access status
- green
- Identifiers
-
- DOI 10.1021/acs.jmedchem.9b00402
- PMID 31260298
- Persistent URL
- https://sonar.ch/global/documents/93020
Statistics
Document views: 34
File downloads:
- Full-text: 0