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Cell Chem Biol. 2018 Aug 23. pii: S2451-9456(18)30270-8. doi: 10.1016/j.chembiol.2018.08.004. [Epub ahead of print]

Small Molecule Targeting of Specific BAF (mSWI/SNF) Complexes for HIV Latency Reversal.

Author information

1
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 201 S. University St., West Lafayette, IN 47907, USA.
2
Department of Biochemistry, Erasmus University Medical Center, Ee634, P.O. Box 2040, 3000CA Rotterdam, the Netherlands.
3
The Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA 02142, USA.
4
Department of Molecular and Cell Biology, Salk Institute for Biological Studies, 10010 N Torrey Pines Road, La Jolla, CA 92037, USA.
5
HHMI and the Departments of Developmental Biology and Pathology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA 94305, USA. Electronic address: crabtree@stanford.edu.
6
Department of Biochemistry, Erasmus University Medical Center, Ee634, P.O. Box 2040, 3000CA Rotterdam, the Netherlands. Electronic address: t.mahmoudi@erasmusmc.nl.
7
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 201 S. University St., West Lafayette, IN 47907, USA. Electronic address: edykhui@purdue.edu.

Abstract

The persistence of a pool of latently HIV-1-infected cells despite combination anti-retroviral therapy treatment is the major roadblock for a cure. The BAF (mammalian SWI/SNF) chromatin remodeling complex is involved in establishing and maintaining viral latency, making it an attractive drug target for HIV-1 latency reversal. Here we report a high-throughput screen for inhibitors of BAF-mediated transcription in cells and the subsequent identification of a 12-membered macrolactam. This compound binds ARID1A-specific BAF complexes, prevents nucleosomal positioning, and relieves transcriptional repression of HIV-1. Through this mechanism, these compounds are able to reverse HIV-1 latency in an in vitro T cell line, an ex vivo primary cell model of HIV-1 latency, and in patient CD4+ T cells without toxicity or T cell activation. These macrolactams represent a class of latency reversal agents with unique mechanism of action, and can be combined with other latency reversal agents to improve reservoir targeting.

KEYWORDS:

ARID1A; BAF complex; HIV-1 latency; SWI/SNF; chromatin remodeling inhibitor; high-throughput screening

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