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

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

JOURNAL=Frontiers in Pharmacology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.00905

DOI=10.3389/fphar.2020.00905

ISSN=1663-9812

ABSTRACT=<p>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)-<italic>N</italic>-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide (compound <bold>15</bold>), <italic>N</italic>-(4-Aminophenyl)heptanamide (<bold>16</bold>), <italic>N</italic>-[4-(Heptanoylamino)phenyl]heptanamide (<bold>17</bold>), and 4-(1,3-Dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)-<italic>N</italic>-(2-hydroxyethyl)butanamide (<bold>18</bold>) inhibit HDAC activity and/or reverse HIV latency <italic>in vitro</italic>. 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.</p>