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

  • Cell Chem Biol. 2018 Dec 20;25(12):1443-1455.e14. doi: 10.1016/j.chembiol.2018.08.004.
Christine A Marian  1 ,  Mateusz Stoszko  2 ,  Lili Wang  3 ,  Matthew W Leighty  3 ,  Elisa de Crignis  2 ,  Chad A Maschinot  1 ,  Jovylyn Gatchalian  4 ,  Benjamin C Carter  1 ,  Basudev Chowdhury  1 ,  Diana C Hargreaves  4 ,  Jeremy R Duvall  3 ,  Gerald R Crabtree  5 ,  Tokameh Mahmoudi  6 ,  Emily C Dykhuizen  7
Affiliations
  • 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: [email protected].
  • 6. Department of Biochemistry, Erasmus University Medical Center, Ee634, P.O. Box 2040, 3000CA Rotterdam, the Netherlands. Electronic address: [email protected].
  • 7. Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 201 S. University St., West Lafayette, IN 47907, USA. Electronic address: [email protected].
PMID: 30197195 DOI: 10.1016/j.chembiol.2018.08.004
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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