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

2018; Elsevier BV; Volume: 25; Issue: 12 Linguagem: Inglês

10.1016/j.chembiol.2018.08.004

2451-9456

Christine Marian, Mateusz Stoszko, Lili Wang, Matthew W. Leighty, Elisa De Crignis, Chad A. Maschinot, Jovylyn Gatchalian, Benjamin C. Carter, Basudev Chowdhury, Diana C. Hargreaves, Jeremy R. Duvall, Robert H. Crabtree, Tokameh Mahmoudi, Emily C. Dykhuizen,

Protein Degradation and Inhibitors

Highlights•HTS identifies a macrolactam that inhibits BAF transcriptional repression•The macrolactams are likely targeting specific ARID1A-containing BAF complexes•The macrolactams reverse HIV-1 latency and are non-toxic to T cells•The macrolactams can be combined with other latency reversal agentsSummaryThe 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.Graphical abstract