HDAC inhibitors(Shandong University)

Disease-modifying and anti-epileptogenic therapies for epilepsy remain limited. Given the critical role of histone deacetylases (HDACs) in epileptogenesis, this study aimed to identify effective HDAC inhibitors and evaluate their anti-epileptogenic potential.

A Mg²⁺-free neuron-like PC12 cell model was used to screen FDA-approved HDAC inhibitors in vitro. Acute and chronic epilepsy models were induced in mice using pentylenetetrazol (PTZ) or kainic acid (KA). Spontaneous recurrent seizures (SRS) were monitored by electroencephalogram (EEG). Neuronal survival, mossy fiber sprouting (MFS), and glial activation were assessed by Nissl staining, Timm staining, and immunofluorescence, respectively. HDAC1 expression was analyzed by Western blot and immunofluorescence. Neuron-specific HDAC1 overexpression was achieved using adeno-associated virus (AAV2; hereafter referred to as AAV)-mediated gene transfer.

Chidamide (Chi) exhibited the most inhibitory effect among nine HDAC inhibitors. Chi significantly reduced seizure susceptibility in acute PTZ- and KA-induced models. In the chronic KA model, Chi attenuated SRS, improved neuronal survival, reduced MFS, and suppressed astrocytic and microglial activation. Chi markedly decreased hippocampal HDAC1 expression, while neuronal HDAC1 overexpression abolished its anti-epileptogenic effects.

Chi attenuates epileptogenesis by inhibiting neuronal HDAC1 and may serve as a promising repurposed anti-epileptogenic therapy.

The goal of this project is to design, synthesize, and test compounds that combine fragments derived from natural products (NPs) for their HIV‐1 latency‐reversal properties, particularly those that act by histone deacetylase inhibition. A fragment library was created by implementing the Retrosynthetic Combinatorial Analysis Procedure (RECAP) on a collection of NPs isolated from different regions in Africa. The top‐scoring docked fragments within the histone deacetylase (HDAC1) binding site were reconstructed to design and synthesize chemical scaffolds that have not been previously described as HDAC inhibitors. Synthesized compounds were then tested for the ability to reverse HIV latency in J‐Lat 10.6 cells and/or inhibit cellular histone deacetylases. The synthesized scaffolds include indole‐chalcones and aminobenzamides. Of fifty‐one synthesized compounds, compound S2‐13 was the most active with HIV latency reversal 20.2% ± 6.2% of J‐Lat 10.6 cells at 10 μg/mL (25.1 μM), which was comparable to the HIV latency‐reversing agent Prostratin. S2‐13 also inhibited HDAC activity with a half‐maximal inhibitory concentration (IC 50 ) of 17.0 μM. We demonstrate that the use of pseudo‐NPs can identify novel chemical scaffolds that can reverse HIV latency and inhibit HDACs in vitro.