Selective Class I HDAC Inhibitors Based on Aryl Ketone
Zinc Binding Induce HIV‑1 Protein for Clearance
Posted on 2020-06-24 - 19:33
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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Liu, Jian; Kelly, Joseph; Yu, Wensheng; Clausen, Dane; Yu, Younong; Kim, Hyunjin; et al. (2020). Selective Class I HDAC Inhibitors Based on Aryl Ketone
Zinc Binding Induce HIV‑1 Protein for Clearance. ACS Publications. Collection. https://doi.org/10.1021/acsmedchemlett.0c00302
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AUTHORS (18)
JL
Jian Liu
JK
Joseph Kelly
WY
Wensheng Yu
DC
Dane Clausen
YY
Younong Yu
HK
Hyunjin Kim
JD
Joseph L. Duffy
CC
Christine C. Chung
RM
Robert W. Myers
SC
Steve Carroll
DK
Daniel J. Klein
JF
James Fells
MH
M. Katharine Holloway
JW
Jin Wu
GW
Guoxin Wu
BH
Bonnie J. Howell
RB
Richard J. O. Barnard
JK
Joseph A. Kozlowski