PCSK9: Regulation and Target for Drug Development for Dyslipidemia.
Annu Rev Pharmacol Toxicol
; 57: 223-244, 2017 01 06.
Article
en En
| MEDLINE
| ID: mdl-27575716
ABSTRACT
Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a secreted zymogen expressed primarily in the liver. PCSK9 circulates in plasma, binds to cell surface low-density lipoprotein (LDL) receptors, is internalized, and then targets the receptors to lysosomal degradation. Studies of naturally occurring PCSK9 gene variants that caused extreme plasma LDL cholesterol (LDL-C) deviations and altered atherosclerosis risk unleashed a torrent of biological and pharmacological research. Rapid progress in understanding the physiological regulation of PCSK9 was soon translated into commercially available biological inhibitors of PCSK9 that reduced LDL-C levels and likely also cardiovascular outcomes. Here we review the swift evolution of PCSK9 from novel gene to drug target, to animal and human testing, and finally to outcome trials and clinical applications. In addition, we explore how the genetics-guided path to PCSK9 inhibitor development exemplifies a new paradigm in pharmacology. Finally, we consider some potential challenges as PCSK9 inhibition becomes established in the clinic.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Sistemas de Liberación de Medicamentos
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Dislipidemias
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Descubrimiento de Drogas
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Proproteína Convertasa 9
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Inhibidores de PCSK9
Límite:
Animals
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Humans
Idioma:
En
Revista:
Annu Rev Pharmacol Toxicol
Año:
2017
Tipo del documento:
Article