Selective Class I HDAC Inhibitors Based on Aryl Ketone Zinc Binding Induce HIV-1 Protein for Clearance
Jian Liu, Joseph Kelly, Wensheng Yu, Dane J. Clausen, Younong Yu, Hyun‐Jin Kim, Joseph Duffy, Christine C. Chung, Robert W. Myers, Steve S. Carroll, Daniel J. Klein, James I. Fells, M. Katharine Holloway, Jin Wu, Guoxin Wu, Bonnie J. Howell, Richard J. O. Barnard, Joseph A. Kozlowski
Abstract
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.