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快乐十分20选8开奖结果:Targeting the NFAT:AP-1 transcriptional complex on DNA with a small-molecule inhibitor
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NFAT:AP-1 cooperation is pivotal for the productive immune response, but when this response is exacerbated, it is implicated in autoimmune and inflammatory diseases. Current immunosuppressive drugs used in clinic, such as cyclosporin A, completely inhibit the NFAT activation and have strong side effects to patients by inhibiting other calcineurin substrates, highlighting the importance of identifying new immunomodulatory drugs. Here, we performed a high-throughput screen and identified Compound 10, a small drug-like molecule that inhibits the NFAT:AP-1:DNA interaction on the ARRE-2 element. Compound 10 does not affect all the NFAT:AP-1 composite sites, but it demonstrates that it is possible to target transcription factor protein complexes on DNA with small molecules, and encourages the study of such molecules for purposes of immunomodulation.
The transcription factor nuclear factor of activated T cells (NFAT) has a key role in both T cell activation and tolerance and has emerged as an important target of immune modulation. NFAT directs the effector arm of the immune response in the presence of activator protein-1 (AP-1), and T cell anergy/exhaustion in the absence of AP-1. Envisioning a strategy for selective modulation of the immune response, we designed a FRET-based high-throughput screen to identify compounds that disrupt the NFAT:AP-1:DNA complex. We screened ～202,000 small organic compounds and identified 337 candidate inhibitors. We focus here on one compound, N-(3-acetamidophenyl)-2-[5-(1H-benzimidazol-2-yl)pyridin-2-yl]sulfanylacetamide (Compound 10), which disrupts the NFAT:AP-1 interaction at the composite antigen-receptor response element-2 site without affecting the binding of NFAT or AP-1 alone to DNA. Compound 10 binds to DNA in a sequence-selective manner and inhibits the transcription of the Il2 gene and several other cyclosporin A-sensitive cytokine genes important for the effector immune response. This study provides proof-of-concept that small molecules can inhibit the assembly of specific DNA–protein complexes, and opens a potential new approach to treat human diseases where known transcription factors are deregulated.
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Author contributions: G.P.M., A.R., and P.G.H. designed research; G.P.M. and S.G. performed research; R.D. provided facilities, guidance, and assistance in designing and performing the high-throughput screen; G.P.M., E.G.-A., R.S., A.G., A.R., and P.G.H. analyzed data; and G.P.M., A.R., and P.G.H. wrote the paper.
Conflict of interest statement: A.R. and P.G.H. are founders of CalciMedica, Inc., and members of its scientific advisory board.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1820604116/-/DCSupplemental.
Published under the PNAS license.