Class I HDAC Inhibitors: Potential New Epigenetic Therapeutics for Alcohol Use Disorder (AUD)

Abstract

Alcohol use disorder (AUD) represents a serious public health issue, and discovery of new therapies is a pressing necessity. Alcohol exposure has been widely demonstrated to modulate epigenetic mechanisms, such as histone acetylation/deacetylation balance, in part via histone deacetylase (HDAC) inhibition. Epigenetic factors have been suggested to play a key role in AUD. To date, 18 different mammalian HDAC isoforms have been identified, and these have been divided into four classes. Since recent studies have suggested that both epigenetic mechanisms underlying AUD and the efficacy of HDAC inhibitors (HDACIs) in different animal models of AUD may involve class I HDACs, we herein report the development of class I HDACIs, including information regarding their structure, potency, and selectivity. More effort is required to improve the selectivity, pharmacokinetics, and toxicity profiles of HDACIs to achieve a better understanding of their efficacy in reducing addictive behavior.

Memory and plasticity impairment after binge drinking in adolescent rat hippocampus: GluN2A/GluN2B NMDA receptor subunits imbalance through HDAC2

“…Animal treatment with MS‐275, an HDACi targeting class I HDAC, reduced motivation to consume EtOH and relapse in heavy drinking rats and reduced binge‐like EtOH drinking in mice, revealing that modulation of epigenetic processes with HDACi is capable to decrease EtOH addiction‐related phenotype. In this context, it has been proposed that targeting epigenetic processes that modulate synaptic plasticity may indeed yield to novel treatments for EtOH addiction . Interestingly, among the 18 isoforms of HDAC, the HDAC2 isoform seems to be particularly implicated in the effects of EtOH as EtOH‐preferring rats knockdown for HDAC2 in the amygdala showed less anxiety‐like behavior and less voluntary EtOH drinking …”

Factors governing the affinity and selectivity of histone deacetylase inhibitors for the HDAC8 enzyme active site: Implications for anticancer therapy

“…Zinccoordinating residues (Asp178, Asp267 and His180) were retained. Tyr306, His142 and His143, which are implicated in contributing to the energetics of the host-guest complexation [12] were retained as well. Hydrogen atoms were added to all the amino acid residues.…”

“…Based on their chemical structure, the HDAC inhibitors (HDACI) of HDAC8 are classified into several chemical classes: hydroxamic acids, benzamides, short chain fatty acids and cyclic tetrapeptides [10]. The hydroxamic acidbased HDACIs have analogous block structure, dictated by the specific geometry of the enzyme and its active site, comprising four pharmacophoric subunits: cap group, connecting unit, hydrocarbon linker and zinc-binding moiety [11,12]. These are shown in Figure 1 along with the structure of the most popular drug of this class -suberoylanilide hydroxamic acid (SAHA).…”

“…Each of the building blocks interacts specifically with a different region of the HDAC enzyme and has its own function. The cap group is usually aromatic and hydrophobic [13] and interacts with the outer layer of the active site [12,14]. The connecting (anilide) unit forms hydrogen bond contacts with amino acid the active site pocket.…”

“…HDAC8 binding site comprises an 11 Ålong channel (tunnel) and 14 Åwide internal cavity [12]. The tunnel's entrance is rigid and its walls are hydrophobic.…”