Bioavailable inhibitors of HIV-1 RNA biogenesis identified through a Rev-based screen

Biochem Pharmacol. 2016 May 1;107:14-28. doi: 10.1016/j.bcp.2016.02.007. Epub 2016 Feb 17.


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.

Keywords: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / adverse effects
  • Anti-HIV Agents / pharmacology*
  • Cell Line
  • Cell Survival / drug effects
  • Clomiphene / adverse effects
  • Clomiphene / pharmacology
  • Cyproheptadine / adverse effects
  • Cyproheptadine / pharmacology
  • Drug Evaluation, Preclinical
  • Gene Expression Regulation, Viral / drug effects*
  • Genes, Reporter / drug effects
  • HIV-1 / drug effects*
  • HIV-1 / growth & development
  • HIV-1 / metabolism
  • High-Throughput Screening Assays
  • Humans
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Protein Interaction Domains and Motifs
  • RNA Splicing / drug effects
  • RNA, Viral / metabolism*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Response Elements / drug effects*
  • Small Molecule Libraries
  • Transcription, Genetic / drug effects*
  • rev Gene Products, Human Immunodeficiency Virus / antagonists & inhibitors*
  • rev Gene Products, Human Immunodeficiency Virus / chemistry
  • rev Gene Products, Human Immunodeficiency Virus / genetics
  • rev Gene Products, Human Immunodeficiency Virus / metabolism


  • Anti-HIV Agents
  • Peptide Fragments
  • RNA, Viral
  • Recombinant Proteins
  • Small Molecule Libraries
  • rev Gene Products, Human Immunodeficiency Virus
  • rev protein, Human Immunodeficiency Virus-1
  • Clomiphene
  • Cyproheptadine