Mechanistic and Structural Insights on Difluoromethyl-1,3,4-oxadiazole Inhibitors of HDAC6.

Histone deacetylase 6 (HDAC6) is increasingly recognized for its potential in targeted disease therapy. This study delves into the mechanistic and structural nuances of HDAC6 inhibition by difluoromethyl-1,3,4-oxadiazole (DFMO) derivatives, a class of non-hydroxamic inhibitors with remarkable selectivity and potency. Employing a combination of nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-mass spectrometry (LC-MS) kinetic experiments, comprehensive enzymatic characterizations, and X-ray crystallography, we dissect the intricate details of the DFMO-HDAC6 interaction dynamics.

The Importance of the "Time Factor" for the Evaluation of Inhibition Mechanisms: The Case of Selected HDAC6 Inhibitors.

Histone deacetylases (HDACs) participate with histone acetyltransferases in the modulation of the biological activity of a broad array of proteins, besides histones. Histone deacetylase 6 is unique among HDAC as it contains two catalytic domains, an -terminal microtubule binding region and a C-terminal ubiquitin binding domain. Most of its known biological roles are related to its protein lysine deacetylase activity in the cytoplasm.

Difluoromethyl-1,3,4-oxadiazoles are slow-binding substrate analog inhibitors of histone deacetylase 6 with unprecedented isotype selectivity.

Histone deacetylase 6 (HDAC6) is an attractive drug development target because of its role in the immune response, neuropathy, and cancer. Knockout mice develop normally and have no apparent phenotype, suggesting that selective inhibitors should have an excellent therapeutic window. Unfortunately, current HDAC6 inhibitors have only moderate selectivity and may inhibit other HDAC subtypes at high concentrations, potentially leading to side effects.

HDAC Inhibition as Potential Therapeutic Strategy to Restore the Deregulated Immune Response in Severe COVID-19.

The COVID-19 pandemic has had a devastating impact worldwide and has been a great challenge for the scientific community. Vaccines against SARS-CoV-2 are now efficiently lessening COVID-19 mortality, although finding a cure for this infection is still a priority. An unbalanced immune response and the uncontrolled release of proinflammatory cytokines are features of COVID-19 pathophysiology and contribute to disease progression and worsening.

Role of Fluorination in the Histone Deacetylase 6 (HDAC6) Selectivity of Benzohydroxamate-Based Inhibitors.

Nonselective histone deacetylase (HDAC) inhibitors show dose-limiting side effects due to the inhibition of multiple, essential HDAC subtypes that can be limited or prevented by restricting their selectivity. We herein report the crystal structures of zebrafish HDAC6 catalytic domain 2 (zHDAC6-CD2) in complex with the selective HDAC6 inhibitors ITF3756 and ITF3985 and shed light on the role of fluorination in the selectivity of benzohydroxamate-based structures over class I isoforms. The reason for the enhancement in the selectivity of the benzohydroxamate-based compounds is the presence of specific interactions between the fluorinated linker and the key residues Gly582, Ser531, and His614 of zHDAC6, which are hindered in class I HDAC isoforms by the presence of an Aspartate that replaces Ser531.

Novel Benzohydroxamate-Based Potent and Selective Histone Deacetylase 6 (HDAC6) Inhibitors Bearing a Pentaheterocyclic Scaffold: Design, Synthesis, and Biological Evaluation.

Histone deacetylase 6 (HDAC6) is a peculiar HDAC isoform whose expression and functional alterations have been correlated with a variety of pathologies such as autoimmune disorders, neurodegenerative diseases, and cancer. It is primarily a cytoplasmic protein, and its deacetylase activity is focused mainly on nonhistone substrates such as tubulin, heat shock protein (HSP)90, Foxp3, and cortactin, to name a few. Selective inhibition of HDAC6 does not show cytotoxic effects in healthy cells, normally associated with the inhibition of Class I HDAC isoforms.

Amino acidic scaffolds bearing unnatural side chains: an old idea generates new and versatile tools for the life sciences.

The unnatural amino acids (UAAs) are members of a class of molecules with relevant impacts in the life sciences. Due to the role of these molecules in the modulation of the chemical and physical properties of biological and inorganic materials, UAAs have attracted increasing interest in recent years. The aim of this review is to highlight (i) the most recent and innovative synthetic routes for the preparation of UAAs, (ii) the recently marketed UAA-based drugs, and (iii) the most promising technological applications involving novel UAA-containing molecular entities.

Cyclic RGD peptidomimetics containing bifunctional diketopiperazine scaffolds as new potent integrin ligands.

The synthesis of eight bifunctional diketopiperazine (DKP) scaffolds is described; these were formally derived from 2,3-diaminopropionic acid and aspartic acid (DKP-1-DKP-7) or glutamic acid (DKP-8) and feature an amine and a carboxylic acid functional group. The scaffolds differ in the configuration at the two stereocenters and the substitution at the diketopiperazinic nitrogen atoms. The bifunctional diketopiperazines were introduced into eight cyclic peptidomimetics containing the Arg-Gly-Asp (RGD) sequence.