Search

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. [ABSTRACT FROM AUTHOR]

The Cover Feature highlights the docking model of lysosomal protective protein cathepsin A (PPCA) and the synthetic derivative of stylissatin A (SA), a cyclic heptapeptide from the Papua New Guinean marine sponge Stylissa sp. Focusing on this new‐found protein–protein interaction inhibition mechanism of SA could lead to the development of new anti‐obesity drugs. More information can be found in the Research Article by M. Kita and co‐workers (DOI: 10.1002/chem.202402049)...By Yiting Sun; Ayumi Dakiiwa; Menghua Zhang; Takahiro Shibata and Masaki KitaReported by Author; Author; Author; Author; Author [Extracted from the article]

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., (© 2024 Wiley-VCH GmbH.)