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00925njm 22002777a 4500 dc Prado, Silvia author Beltran, Manuela author Coiras, Mayte author Bedoya, Luis M author Alcamí, José author Gallego, José author 2016-05-01 New antiretroviral agents with alternative mechanisms are needed to complement the combination therapies used to treat HIV-1 infections. Here we report the identification of bioavailable molecules that interfere with the gene expression processes of HIV-1. The compounds were detected by screening a small library of FDA-approved drugs with an assay based on measuring the displacement of Rev, and essential virus-encoded protein, from its high-affinity RNA binding site. The antiretroviral activity of two hits was based on interference with post-integration steps of the HIV-1 cycle. Both hits inhibited RRE-Rev complex formation in vitro, and blocked LTR-dependent gene expression and viral transcription in cellular assays. The best compound altered the splicing pattern of HIV-1 transcripts in a manner consistent with Rev inhibition. This mechanism of action is different from those used by current antiretroviral agents. The screening hits recognized the Rev binding site in the viral RNA, and the best compound did so with substantial selectivity, allowing the identification of a new RNA-binding scaffold. These results may be used for developing novel antiretroviral drugs. Biochem Pharmacol. 2016 May 1;107:14-28. 10.1016/j.bcp.2016.02.007 1873-2968 0006-2952 Biochemical pharmacology 26896646 http://hdl.handle.net/20.500.12105/10274 Ciprofloxacin (PubChem CID: 2764) Clomiphene (PubChem CID: 1548953) Cyproheptadine (PubChem CID: 2913) Homochlorcyclizine (PubChem CID: 3627) Human immunodeficiency virus type 1 Mitoxantrone (PubChem CID: 4212) Neamine (PubChem CID: 72392) Neomycin B (PubChem CID: 8378) RNA Rev Screen Transcription Bioavailable inhibitors of HIV-1 RNA biogenesis identified through a Rev-based screen