title: Rilpivirine analogs potently inhibit drug-resistant HIV-1 mutants.
abstract: BACKGROUND
  Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are a class of antiretroviral compounds that bind in an allosteric binding pocket in HIV-1 RT, located about 10 Å from the polymerase active site. Binding of an NNRTI causes structural changes that perturb the alignment of the primer terminus and polymerase active site, preventing viral DNA synthesis. Rilpivirine (RPV) is the most recent NNRTI approved by the FDA, but like all other HIV-1 drugs, suboptimal treatment can lead to the development of resistance. To generate better compounds that could be added to the current HIV-1 drug armamentarium, we have developed several RPV analogs to combat viral variants that are resistant to the available NNRTIs.
  
  
  RESULTS
  Using a single-round infection assay, we identified several RPV analogs that potently inhibited a broad panel of NNRTI resistant mutants. Additionally, we determined that several resistant mutants selected by either RPV or Doravirine (DOR) caused only a small increase in susceptibility to the most promising RPV analogs.
  
  
  CONCLUSIONS
  The antiviral data suggested that there are RPV analogs that could be candidates for further development as NNRTIs, and one of the most promising compounds was modeled in the NNRTI binding pocket. This model can be used to explain why this compound is broadly effective against the panel of NNRTI resistance mutants.
authors.affiliation: HIV Drug Resistance Program, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD, USA. smithsj2@mail.nih.gov.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Smith
authors.affiliation: Chemical Biology Laboratory, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD, USA. paulyg@mail.nih.gov.
authors.forename: Gary T
authors.initials: GT
authors.lastname: Pauly
authors.affiliation: HIV Drug Resistance Program, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD, USA. aamirakram19@yahoo.com.
authors.forename: Aamir
authors.initials: A
authors.lastname: Akram
authors.affiliation: Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. kpm20@pitt.edu.
authors.forename: Kevin
authors.initials: K
authors.lastname: Melody
authors.affiliation: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, NIH, 9800 Medical Center Drive, Bethesda, MD, 3370, USA. bantukallug@mail.nih.gov.
authors.forename: Ganesha
authors.initials: G
authors.lastname: Rai
authors.affiliation: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, NIH, 9800 Medical Center Drive, Bethesda, MD, 3370, USA. maloneyd@mail.nih.gov.
authors.forename: David J
authors.initials: DJ
authors.lastname: Maloney
authors.affiliation: Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. zaa4@mail.nih.gov.|Division of Infectious Diseases, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. zaa4@mail.nih.gov.
authors.forename: Zandrea
authors.initials: Z
authors.lastname: Ambrose
authors.affiliation: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, NIH, 9800 Medical Center Drive, Bethesda, MD, 3370, USA. craigt@mail.nih.gov.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Thomas
authors.affiliation: Chemical Biology Laboratory, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD, USA. joel.schneider@mail.nih.gov.
authors.forename: Joel T
authors.initials: JT
authors.lastname: Schneider
authors.affiliation: HIV Drug Resistance Program, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD, USA. hughesst@mail.nih.gov.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Hughes
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation; D000068696:Rilpivirine / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D000068696:Rilpivirine