Advances in the Mechanistic Study of the Control of Oxidative Stress Injury by Modulating HDAC6 Activity

Abstract

Oxidative stress is defined as an injury resulting from a disturbance in the dynamic equilibrium of the redox environment due to the overproduction of active/radical oxygen exceeding the antioxidative ability of the body. This is a key step in the development of various diseases. Oxidative stress is modulated by different factors and events, including the modification of histones, which are the cores of nucleosomes. Histone modification includes acetylation and deacetylation of certain amino acid residues; this process is catalyzed by different enzymes. Histone deacetylase 6 (HDAC6) is a unique deacetylating protease that also catalyzes the deacetylation of different nonhistone substrates to regulate various physiologic processes. The intimate relationship between HDAC6 and oxidative stress has been demonstrated by different studies. The present paper aims to summarize the data obtained from a mechanistic study of HDAC6 and oxidative stress to guide further investigations on mechanistic characterization and drug development.

Pioneering first‐in‐class FAAH‐HDAC inhibitors as potential multitarget neuroprotective agents

“…Initially, the newly synthesized compounds were tested against FAAH and HDAC6, selecting this peculiar HDAC isoform due to its major involvement in oxidative stress‐related CNS diseases. [ 40 ] The selectivity profile of the most promising compounds was assessed by testing them against h HDAC isoforms 1, 8, 10, and h MAGL, as reported in Table 2. The experimental results were rationalized by computational studies, performed by applying a docking protocol against FAAH and HDAC6 enzymes.…”

“…[30] In the frame of our research interest in the development of MTDLs for treating CNS diseases, [31][32][33][34][35][36] we recently exploited the ECS modulation for developing different classes of MTDLs, such as MAGL/FAAH dual inhibitors [37] and FAAH/D3 modulators. [16] Our expertise in the design of HDACis [21,38,39] and their emerging protecting role against oxidative stress [40] inspired the development of novel modulators of both the ECS and epigenetic regulation as potential neuroprotective agents.…”