期刊
FRONTIERS IN PHARMACOLOGY
卷 11, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2020.00905
关键词
virtual screening; histone deacetylase; histone deacetylase inhibitor; HIV; latency reversal; drug discovery
资金
- Canadian Institutes for Health Research [CIHR PJT-153057]
- New Frontiers in Research Fund - Explorations [NFRFE-2018-01386]
- Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE)
- DELTAS African Initiative [DEL-15-006]
- New Partnership for Africa's Development Planning and Coordinating Agency (NEPAD Agency)
- Wellcome Trust [107752/Z/15/Z]
- UK government
- Simon Fraser University -Social Sciences and Humanities Research Council of Canada (SSHRC) Undergraduate Research Student Award
- German Academic Exchange Services (DAAD), Germany
- CIHR Frederick Banting and Charles Best MSc Award
- Rideau Hall Foundation
- Community Foundations of Canada
- Alexander von Humboldt Foundation, Germany
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 (compound15),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 latencyin 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.
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