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Cited by 54HIV/AIDS drug development and treatmentHIV Research and TreatmentComputational Drug Discovery Methods

Inhibitors of HIV-1 Reverse Transcriptase—Associated Ribonuclease H Activity

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Ilina, Tatiana, LaBarge, Krystal, Sarafianos, Stefan G., Ishima, Rieko, Parniak, Michael A.·2012·Biology
DOI 10.3390/biology1030521PMC PMC3627382
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Abstract

HIV-1 enzyme reverse transcriptase (RT) is a major target for antiviral drug development, with over half of current FDA-approved therapeutics against HIV infection targeting the DNA polymerase activity of this enzyme. HIV-1 RT is a multifunctional enzyme that has RNA and DNA dependent polymerase activity, along with ribonuclease H (RNase H) activity. The latter is responsible for degradation of the viral genomic RNA template during first strand DNA synthesis to allow completion of reverse transcription and the viral dsDNA. While the RNase H activity of RT has been shown to be essential for virus infectivity, all currently used drugs directed at RT inhibit the polymerase activity of the enzyme; none target RNase H. In the last decade, the increasing prevalence of HIV variants resistant to clinically used antiretrovirals has stimulated the search for inhibitors directed at stages of HIV replication different than those targeted by current drugs. HIV RNase H is one such novel target and, over the past few years, significant progress has been made in identifying and characterizing new RNase H inhibitor pharmacophores. In this review we focus mainly on the most potent low micromolar potency compounds, as these provide logical bases for further development. We also discuss why HIV RNase H has been a difficult target for antiretroviral drug development.

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  • Several pharmacophores for ribonuclease H active-site inhibitors are diketo acid, N-hydroxyimide, hydroxytropolone, pyrimidinol carboxylic acid, N-hydroxy naphthyridinone, pyrido-pyrimidinone, nitrofuran-2-carboxylic acid, and thiocarbamates.

    “Several pharmacophores for RNH active site inhibitors are: diketo acid, N-hydroxyimide, hydroxytropolone, pyrimidinol carboxylic acid, N-hydroxy naphthyridinone, pyrido-pyrimidinone, nitrofuran-2-carboxylic acid and thiocarbamates [31,32].”

    From Retroviral RNase H: structure, mechanism, and inhibition (2021) · cites this paper as [31]

    Section 3.1 (Table 1; page not provided) discusses diketo acids, N-hydroxyimides, tropolones, pyrimidinol carboxylic acids, N-hydroxy naphthyridinones, and pyrido-pyrimidinones as RNase H active-site inhibitor classes. The copy does not identify nitrofuran-2-carboxylic acid as such a class, and Section 3.2 (Table 2; page not provided) places thiocarbamates under allosteric, rather than active-site, inhibitors. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • To determine whether positive hits inhibit only ribonuclease H or also polymerase or integrase strand transfer, the compounds are also assessed against those two enzymes.

    “To identify whether positive hits of compound screens inhibit only the RNH activity or also inhibit polymerase or IN strand transfer (INST) activity, these two enzymes are also assessed for inhibition by the screened compounds [31].”

    From Retroviral RNase H: structure, mechanism, and inhibition (2021) · cites this paper as [31]

    Section 3.1 (Table 1; page unavailable) compares RNase H inhibitor activity with RT polymerase and integrase activity, supporting assessment of whether compounds inhibit other HIV enzymes. But some entries have no reported result, and the paper does not establish that all positive screening hits are assessed against both enzymes or specify an integrase strand-transfer assay. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • The two-metal-binding mechanism has been widely accepted based on structural and functional experiments.

    “Based on these structural and functional experiments, the two metal-binding mechanism has been widely accepted [27,28,30,31,63,64].”

    From Retroviral RNase H: structure, mechanism, and inhibition (2021) · cites this paper as [31]

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Research works printed but not linked: 51

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Cited by

Sorted by citations

Authors
Ilina, T., LaBarge, K., Sarafianos, S. G., Ishima, R., & Parniak, M. A.
Affiliations
  • University of Pittsburgh (US)
  • University of Missouri (US)
Corresponding author
Parniak, Michael A.
ORCID
Venue
Biology
Publisher
MDPI AG
Published
2012-10-19
Volume
1
Issue
3
Pages
521-541
ISSN
2079-7737 (ISSN-L)
DOI
10.3390/biology1030521
PMC
PMC3627382
OpenAlex
W1969250806
Cited by
54
References
4
Citations by year
2026: 1 · 2025: 4 · 2024: 1 · 2023: 2 · 2022: 4 · 2021: 6 · 2020: 3 · 2019: 3 · 2018: 3 · 2017: 4 · 2016: 4 · 2015: 4 · 2014: 11 · 2013: 3 · 2012: 1
FWCI
4.22
Type
journal article
Language
en
Open access
Licence
Locations
  • Biology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (AI073975)
  • National Institute of Allergy and Infectious Diseases (R01AI077424, R01AI100890, U19AI073975)
Topics
  • Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
  • Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
Keywords
HIV-1 reverse transcriptase, RNase H, RNase H inhibitors, antiretroviral drug development, HIV drug resistance, viral RNA degradation, reverse transcription, pharmacophore

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