Biophysical Insights into the Inhibitory Mechanism of Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors

HIV-1 reverse transcriptase (RT) plays a central role in HIV infection. Current United States Federal Drug Administration (USFDA)-approved antiretroviral therapies can include one of five approved non-nucleoside RT inhibitors (NNRTIs), which are potent inhibitors of RT activity. Despite their crucial clinical role in treating and preventing HIV-1 infection, their mechanism of action remains elusive. In this review, we introduce RT and highlight major advances from experimental and computational biophysical experiments toward an understanding of RT function and the inhibitory mechanism(s) of NNRTIs.

• Publication year

  2013

• Venue

  Biomolecules

• Publication date

  2013-11-01

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.3390/biom3040889PMID 24970195PMCID 4030976
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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• Thermodynamics of HIV-1 reverse transcriptase in action elucidates the mechanism of action of non-nucleoside inhibitors.

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• Thumbs down for HIV: domain level rearrangements do occur in the NNRTI-bound HIV-1 reverse transcriptase.

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• HIV-1 reverse transcription.

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• A toolkit and benchmark study for FRET-restrained high-precision structural modeling

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• Human Immunodeficiency Virus Reverse Transcriptase: 25 Years of Research, Drug Discovery, and Promise*

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  2011influential reference
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  2011cited by this paper
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  2010cited by this paper
• Accurate single-molecule FRET studies using multiparameter fluorescence detection.

  2010cited by this paper
• Non-nucleoside reverse transcriptase inhibitors (NNRTIs), their discovery, development, and use in the treatment of HIV-1 infection: a review of the last 20 years (1989-2009).

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• Reverse transcriptase in motion: conformational dynamics of enzyme-substrate interactions.

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  2010influential reference
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  2010cited by this paper
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• Solution structural dynamics of HIV-1 reverse transcriptase heterodimer.

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  2009influential reference
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  2008influential reference
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  2007cited by this paper
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• Interaction kinetic characterization of HIV-1 reverse transcriptase non-nucleoside inhibitor resistance.

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• Elastic network models for understanding biomolecular machinery: from enzymes to supramolecular assemblies

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• Efavirenz enhances the proteolytic processing of an HIV‐1 pol polyprotein precursor and reverse transcriptase homodimer formation

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  2002influential reference
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• Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors

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  1992influential reference
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