Selective Class I HDAC Inhibitors Based on Aryl KetoneZinc Binding Induce HIV‑1 Protein for Clearance
2020
HIV persistence in
latently infected, resting CD4+ T
cells is broadly considered a barrier to eradicate HIV. Activation
of the provirus using latency-reversing agents (LRAs) followed by
immune-mediated clearance to purge reservoirs has been touted as a
promising therapeutic approach. Histone deacetylases (HDACs) and histone
acetyltransferases (HATs) control the acetylation level of lysine
residues in histones to regulate the gene transcription. Several clinical
HDAC inhibitors had been examined as LRAs, which induced HIV activation
in vitro and in vivo. Here we report the discovery of a series of
selective and potent class I HDAC inhibitors based on aryl ketones
as a zinc binding group, which reversed HIV latency using a Jurkat
model of HIV latency in 2C4 cells. The SAR led to the discovery of
a highly selective class I HDAC inhibitor 10 with excellent
potency. HDACi 10 induces the HIV gag P24 protein in patient latent CD4+ T cells.
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