Novel Histone Deacetylase Inhibitors and HIV-1 Latency-Reversing Agents Identified by Large-Scale Virtual Screening.

Donya Naz Divsalar,Fidele Ntie-Kang,Cole Schonhofer,Conrad Veranso Simoben,Ian Tietjen,Wolfgang Sippl,Khumoekae Richard

doi:10.3389/fphar.2020.00905

Abstract

Current antiretroviral therapies used for HIV management do not target latent viral reservoirs in humans. The experimental “shock-and-kill” therapeutic approach involves use of latency-reversal agents (LRAs) that reactivate HIV expression in reservoir-containing cells, followed by infected cell elimination through viral or host immune cytopathic effects. Several LRAs that function as histone deacetylase (HDAC) inhibitors are reported to reverse HIV latency in cells and in clinical trials; however, none to date have consistently reduced viral reservoirs in humans, prompting a need to identify new LRAs. Toward this goal, we describe here a virtual screening (VS) approach which uses 14 reported HDAC inhibitors to probe PubChem and identifies 60 LRA candidates. We then show that four screening “hits” including (S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide (compound 15), N-(4-Aminophenyl)heptanamide (16), N-[4-(Heptanoylamino)phenyl]heptanamide (17), and 4-(1,3-Dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)-N-(2-hydroxyethyl)butanamide (18) inhibit HDAC activity and/or reverse HIV latency in vitro. This study demonstrates and supports that VS-based approaches can readily identify novel HDAC inhibitors and LRAs, which in turn may help toward inhibitor design and chemical optimization efforts for improved HIV shock-and-kill-based efforts.

Highlights

While combination antiretroviral therapy can durably suppress HIV replication, it does not act on resting CD4+ T cells containing latent proviral reservoirs
These results suggest that additional histone deacetylases (HDAC) inhibitors with improved efficacy and/or selectivity for proviral integration sites may be needed to achieve sufficient HIV latency reversal and viral reservoir clearance in vivo
All selected compounds were reported to reverse HIV latency in one or more in vitro and/or primary cell assays with the exception of serpulanine A (Williams et al, 2018), which we confirmed at 10 μM induced a 31.0% increase in HIV provirus expression, as measured by the GFP reporter, in J-Lat 10.6 cells (Jordan et al, 2003 and see below)

Summary

Introduction

While combination antiretroviral therapy (cART) can durably suppress HIV replication, it does not act on resting CD4+ T cells containing latent proviral reservoirs. While a subset of these studies reports transient increases of virus or viral RNA following HDAC inhibitor administration, no trial to date has shown a significant reduction of HIV reservoir size in humans (Abner and Jordan, 2019; Zerbato et al, 2019). These results suggest that additional HDAC inhibitors with improved efficacy and/or selectivity for proviral integration sites may be needed to achieve sufficient HIV latency reversal and viral reservoir clearance in vivo

Methods

Results

Conclusion