HIV persistence in latently infected, resting CD4<sup>+</sup> T cells is broadly considered a barrier to eradicate HIV. Activation of provirus from latently infected cells using latency-reversing agents (LRAs) followed by immune-mediated clearance to purge reservoirs was confirmed to be promising therapeutic approaches. Histone deacetylases (HDACs) and histone acetyltransferases (HATs) control the acetylation level of lysine residues in histones to regulate the gene transcription. The deacetylation leads to a more condensed chromatin structure, reducing the gene transcription. Thus HDAC inhibitors can increase the gene transcription and several HDAC inhibitors (vorinostat and panobinostat) had been examined as LRAs which induced HIV protein expression on CD4<sup>+</sup> T cells. In this presentation, we are going to report the discovery of a series of selective and potent class I HDAC inhibitors based on aryl ketone as zinc binding group. SAR led to the discovery of a highly selective class I HDAC inhibitor with excellent potency in both enzymatic and cellular assays. This HDAC inhibitor also induces the expression of HIV gag P24 in the patient latent T cells.

Selective class I HDAC inhibitors based on aryl ketone zinc binding induce HIV-1 protein for clearance

2019 Fall National Meeting

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