Open AccessSelective Class I HDAC Inhibitors Based on Aryl Ketone Zinc Binding Induce HIV-1 Protein for Clearance
Author(s) -
Jian Liu,
Joseph Kelly,
Wei Yu,
Dane J. Clausen,
Youg Yu,
HyunJin Kim,
Joseph Duffy,
Caroline Chung,
Robert W. Myers,
Steve Carroll,
Daniel Klein,
James I. Fells,
M. Katharine Holloway,
Wei Jin,
Guoxin Wu,
Bonnie Howell,
Richard Barnard,
Joseph A. Kozlowski
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00302
Subject(s) - provirus , acetylation , histone deacetylase , in vivo , in vitro , zinc finger , human immunodeficiency virus (hiv) , chemistry , histone , biology , cancer research , biochemistry , virology , transcription factor , gene , genetics , genome
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.