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Biological Evaluation And In Silico Study Of Benzoic Acid Derivatives From Bjerkandera Adusta Targeting Proteostasis Network Modules

Katerina Georgousaki, Nikolaos Tsafantakis, Sentiljana Gumeni, George Lambrinidis, Victor González-Menéndez, Jose R. Tormo, Olga Genilloud, Ioannis P. Trougakos, Nikolas Fokialakis

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A main cellular functional module that becomes dysfunctional during aging is the proteostasis network. In the present study, we show that benzoic acid derivatives isolated from Bjerkandera adusta promote the activity of the two main protein degradation systems, namely the ubiquitin-proteasome (UPP) and especially the autophagy-lysosome pathway (ALP) in human foreskin fibroblasts. Our findings were further supported by in silico studies, where all compounds were found to be putative binders of both cathepsins B and L. Among them, compound 3 (3-chloro-4-methoxybenzoic acid) showed the most potent interaction with both enzymes, which justifies the strong activation of cathepsins B and L (467.3 ± 3.9%) on cell-based assays. Considering that the activity of both the UPP and ALP pathways decreases with aging, our results suggest that the hydroxybenzoic acid scaffold could be considered as a promising candidate for the development of novel modulators of the proteostasis network, and likely of anti-aging agents.