Computationally Driven Structure Optimization, Synthesis, and Biological Evaluation of Imidazole-Based Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Inhibitors.
J Med Chem
; 62(13): 6163-6174, 2019 07 11.
Article
en En
| MEDLINE
| ID: mdl-31260298
ABSTRACT
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Inhibidores de Proteasas
/
Peptidomiméticos
/
Inhibidores de PCSK9
/
Imidazoles
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2019
Tipo del documento:
Article
País de afiliación:
Italia