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Retrovirology. 2016 Feb 16;13:11. doi: 10.1186/s12977-016-0244-2.

Rilpivirine analogs potently inhibit drug-resistant HIV-1 mutants.

Author information

1
HIV Drug Resistance Program, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD, USA. smithsj2@mail.nih.gov.
2
Chemical Biology Laboratory, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD, USA. paulyg@mail.nih.gov.
3
HIV Drug Resistance Program, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD, USA. aamirakram19@yahoo.com.
4
Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. kpm20@pitt.edu.
5
NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, NIH, 9800 Medical Center Drive, Bethesda, MD, 3370, USA. bantukallug@mail.nih.gov.
6
NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, NIH, 9800 Medical Center Drive, Bethesda, MD, 3370, USA. maloneyd@mail.nih.gov.
7
Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. zaa4@mail.nih.gov.
8
Division of Infectious Diseases, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. zaa4@mail.nih.gov.
9
NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, NIH, 9800 Medical Center Drive, Bethesda, MD, 3370, USA. craigt@mail.nih.gov.
10
Chemical Biology Laboratory, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD, USA. joel.schneider@mail.nih.gov.
11
HIV Drug Resistance Program, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD, USA. hughesst@mail.nih.gov.

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.

PMID:
26880034
PMCID:
PMC4754833
DOI:
10.1186/s12977-016-0244-2
[Indexed for MEDLINE]
Free PMC Article

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