Series of Novel and Highly Potent Cyclic Peptide PCSK9 Inhibitors Derived from an mRNA Display Screen and Optimized via Structure-Based Design.
J Med Chem
; 63(22): 13796-13824, 2020 11 25.
Article
em En
| MEDLINE
| ID: mdl-33170686
ABSTRACT
Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is a key regulator of plasma LDL-cholesterol (LDL-C) and a clinically validated target for the treatment of hypercholesterolemia and coronary artery disease. In this paper, we describe a series of novel cyclic peptides derived from an mRNA display screen which inhibit the protein-protein interaction between PCSK9 and LDLR. Using a structure-based drug design approach, we were able to modify our original screening lead 2 to optimize the potency and metabolic stability and minimize the molecular weight to provide novel bicyclic next-generation PCSK9 inhibitor peptides such as 78. These next-generation peptides serve as a critical foundation for continued exploration of potential oral, once-a-day PCSK9 therapeutics for the treatment of cardiovascular disease.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
RNA Mensageiro
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Desenho de Fármacos
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Inibidores Enzimáticos
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Pró-Proteína Convertase 9
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Inibidores de PCSK9
Limite:
Animals
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Female
/
Humans
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Male
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article