Inhibition of Lysosomal Cathepsin A and Neuraminidase 1 Interaction by Anti-obesity Cyclic Peptide.
Chemistry
; : e202402049, 2024 Aug 08.
Article
en En
| MEDLINE
| ID: mdl-39115037
ABSTRACT
Chronic inflammation in adipose tissue is associated with metabolic disorders such as obesity and type 2 diabetes. Novel small molecules targeting adipocyte differentiation and fat accumulation offer potential for new anti-inflammatory and anti-obesity drugs. Here we show that the marine cyclic heptapeptide stylissatin A and its analogs (SAs) inhibit membranous neuraminidase 1 (Neu1) function by interacting with lysosomal protective protein cathepsin A (PPCA). Neu1 has been less explored as a therapeutic target due to the genetic defects leading to neurodegenerative disorders. However, unlike traditional neuraminidase inhibitors, SAs don't directly bind to Neu1 but modulate the molecular chaperone activity of PPCA. SAs caused degradation of perilipin 1 around lipid droplets and inhibited fat accumulation, along with decrease in membranous Neu1. Molecular docking and molecular dynamics simulations revealed that SAs interacted with activated PPCA at the Neu1 binding site. Focusing on this newfound protein-protein interaction inhibition mechanism could lead to the development of pharmaceuticals with fewer side effects.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
Chemistry
Asunto de la revista:
QUIMICA
Año:
2024
Tipo del documento:
Article
País de afiliación:
Japón
Pais de publicación:
Alemania