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Cited by 15HIV/AIDS drug development and treatmentHIV Research and TreatmentEnzyme Structure and Function

Retroviral RNase H: structure, mechanism, and inhibition

Open access
Tatiana V. Ilina, Teresa A. Brosenitsch, Nicolas Sluis‐Cremer, Rieko Ishima·2021·The Enzymes
DOI 10.1016/bs.enz.2021.07.007PMC PMC8994160
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Abstract

All retroviruses encode the enzyme, reverse transcriptase (RT), which is involved in the conversion of the single-stranded viral RNA genome into double-stranded DNA. RT is a multifunctional enzyme and exhibits DNA polymerase and ribonuclease H (RNH) activities, both of which are essential to the reverse-transcription process. Despite the successful development of polymerase-targeting antiviral drugs over the last three decades, no bona fide inhibitor against the RNH activity of HIV-1 RT has progressed to clinical evaluation. In this review article, we describe the retroviral RNH function and inhibition, with primary consideration of the structural aspects of inhibition.

Integrity signals

Registry

Crossref · 10.1016/bs.enz.2021.07.007

Cites

126 of 126 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

40 of 106 cited sources checked · 13 supported · 2 flagged · accuracy not yet measured

  • Premisecitation

    Ribonuclease H belongs to the retroviral integrase superfamily.

    “Structurally, RNH belongs to the retroviral integrase superfamily [19,23,24]”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [19] source

      The section on vertebrate retroviruses reacquiring their RNH domain describes a structural fold and catalytic features shared by RNH and retroviral integrases. It does not classify RNH as a member of a retroviral integrase superfamily, so the structural connection is supported but the stated membership is not. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [23] source
    • cites [24] source
      Experimental — accuracy not yet measured
  • Premisecitation

    The connection, ribonuclease H, and integrase domains share a similar RNH-like fold consisting of a five-stranded beta-sheet with alpha-helices.

    “the connection, RNH, and IN domains that are encoded in retroviral Pol (Figure 1a) share a similar RNH-like fold, a five stranded β–sheet with α–helices [19,23,24]”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [19] source
      Experimental — accuracy not yet measured
    • cites [23] source
    • cites [24] source

      The Introduction describes a conserved RNase H-like fold in integrase-superfamily catalytic domains, with a five-stranded β-sheet and α-helices, and identifies both RNase H and integrase as members. It does not establish that the retroviral Pol connection domain shares this fold. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    Catalytic activity of rnhA ribonuclease H proteins requires an active-site DEDD motif and a conserved active-site histidine.

    “For the catalytic activity of rnhA RNH proteins, site-directed mutagenesis, thermal stability and structural determination studies have indicated that an active-site DEDD motif and conserved active-site histidine are required [43-50]”
    Quote in the paperNot a substantial claim3 of 8 sources checked
    • cites [43] source

      The Molecular modeling section identifies D443, E478, D498 and D549 as essential active-site residues for HIV reverse transcriptase–associated RNase H. It says an interaction involving H539 may affect catalytic efficiency, but does not establish that histidine is required. The paper addresses HIV RT-associated RNase H, not rnhA proteins; page numbers are unavailable in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [44] source
    • cites [45] source

      The Introduction says HIV-1 RNase H shares an active-site architecture with bacterial RNase H enzymes, and the Results identify E478 as catalytic and suggest that D498N may prevent formation of a catalytic complex. Our copy does not establish that rnhA proteins require a DEDD motif or a conserved active-site histidine for catalytic activity. Page numbers were not available in the indexed passages. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [46] source
    • cites [47] source

      The Results (Biochemical characterization; page unavailable) identify the Ty3 reverse transcriptase D426N variant as RNase H-deficient, supporting a role for an aspartate residue in this enzyme’s activity. The paper does not establish that rnhA proteins require a DEDD motif or a conserved active-site histidine. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [48] source
    • cites [49] source
    • cites [50] source
  • Premisecitation

    Two models for metal coordination in the HIV-1 ribonuclease H endonuclease reaction have been proposed: one involving a single ion and one involving two metal ions.

    “In HIV-1 RNH, two different models for metal coordination in the endonuclease reaction have been proposed, one that invokes binding by a single ion [47,59] (Figure 3c and 3d) and one that invokes binding by two metal ions [50,60-62] (Figure 3b).”
    Quote in the paperNot a substantial claim1 of 6 sources checked
    • cites [47] source

      The Results section on the RNase H domain discusses substrate cleavage and compares Ty3 with HIV-1 RT, but does not describe competing single-ion and two-metal-ion coordination models. Searches for those models and for metal-dependent catalysis found no passage in our copy that addresses the claim. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [59] source
    • cites [50] source
    • cites [60] source
    • cites [61] source
    • cites [62] source
  • Premisecitation

    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].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [31] source

      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
    • cites [32] source

      The Metal-chelating active site inhibitors sections discuss diketo acids, N-hydroxyimides, hydroxytropolones, pyrimidinol carboxylic acids, N-hydroxynaphthyridinones, nitrofuran derivatives, and thiocarbamates. The copy does not identify a pyrido-pyrimidinone active-site inhibitor; it instead discusses thienopyrimidinones under Allosteric RNaseH inhibitors. Page numbers were not available in the indexed passages. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • May combine two claims. 22
  • Classified as probably not a substantial claim. 4

  • May combine two claims.

    Premisecitation

    The crystal structure of S. cerevisiae Ty3 reverse transcriptase shows the ribonuclease H domain at a position corresponding to the connection domain and interacting with an RNA/DNA hybrid.

    “A crystal structure of the LTR retrotransposon RT of S. cerevisiae Ty3, which belongs to the Gypsy family of retrotransposons, demonstrates that the RNH domain locates at a position corresponding to that of the connection domain and interacts with RNA/DNA hybrid [42].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [42] source

      The Abstract identifies the reported crystal structure as Moloney murine leukemia virus (MMLV) reverse transcriptase, not S. cerevisiae Ty3 reverse transcriptase. The Results and Discussion describe the positions of domains in MMLV RT; they do not establish the claimed Ty3 RNase H position or its interaction with an RNA/DNA hybrid. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Non-directed or internal cleavages occur within larger RNA/DNA duplex segments and may depend in part on the RNA sequence.

    “Non-directed or internal cleavages take place within larger segments of RNA/DNA duplex and might depend, in part, on the sequence of the RNA [28,52,55].”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [28] source
    • cites [52] source
    • cites [55] source

      The Introduction (page unavailable) describes RNase H as an endonuclease that cleaves RNA in RNA/DNA hybrids, consistent with internal cleavage. But it explicitly says cleavage occurs in a “sequence nonspecific manner,” contrary to the claim that it might depend in part on RNA sequence. The crystallographic-design section discusses duplex lengths and nick positions, not sequence-dependent cleavage. (LLM, conf=0.82)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Reverse transcriptase possesses both DNA polymerase and ribonuclease H activities, and both are required for reverse transcription and the viral life cycle.

    “RT is a multifunctional enzyme and exhibits DNA polymerase and ribonuclease H (RNH) activities, both of which are essential to the reverse-transcription process.”
    • Also stated in: § Introduction · plain
      “RT has DNA polymerase and ribonuclease H (RNH) activities, both of which are critical during the viral life cycle [1,2].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [1]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [2] source

      The Introduction (‘Madison, 1970’; page not provided) identifies reverse transcriptase as the enzyme responsible for making the provirus and describes its DNA polymerase activity. Our copy does not establish that it has ribonuclease H activity or that both activities are essential to reverse transcription or the viral life cycle (searched: ribonuclease H, RNase H, and required activities). (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    M-MLV ribonuclease H has 22% sequence identity with HIV-1 ribonuclease H and shows higher catalytic activity with Mn2+ than with Mg2+.

    “while M-MLV RNH, which has 22 % sequence identity with HIV-1 RNH, exhibits higher catalytic activity in the presence of Mn2+ compared to Mg2+ [58].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [58] source

      The Abstract describes physical mapping of HIV-1 reverse transcriptase on RNA primers, and the Experimental Procedures describe assays using MgCl2. Neither passage addresses M-MLV RNase H sequence identity or compares its catalytic activity with Mn2+ versus Mg2+; searches for those terms found no relevant passage in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    HTPD has a ribonuclease H IC50 below micromolar, antiviral EC50 in the micromolar range, and CC50 above 100 micromolar.

    “HTPD exhibited an RNH IC50 below μM, antiviral EC50 in the μM range and CC50 above 100 μM [87].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [87] source

      The Results and Discussion sections report RNase H inhibition and antiviral activity for pyrrolyl diketo acid derivatives, but do not identify HTPD or give measurements for it. The Cell-Based Assays section reports CC50 >50 μM for the compounds studied, not a CC50 >100 μM for HTPD. Searches for HTPD and the claimed values found no passage that verifies its three measurements. (LLM, conf=0.74)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    5'-end RNA-directed cleavage is determined by the position of 5'-recessed RNA in the DNA polymerase active site and removes longer RNA fragments still base-paired to the minus DNA.

    “The 5'-end RNA-directed cleavage is determined by the position of the 5’-recessed RNA (from nicks) in the DNA polymerase active site and removes longer RNA fragments that remain base-paired to the minus DNA [26-28,52-54].”
    Quote in the paperNot a substantial claim1 of 6 sources checked
    • cites [26] source
    • cites [27] source
    • cites [28] source

      The “RNA 5' end-directed cleavage” section says reverse transcriptase binds a hybrid with a recessed RNA 5' end and cleaves the RNA about 13–19 nucleotides from that end; it proposes an interaction near the polymerase active site. But the same section explicitly says an RNA 5' end at a nick is not recognized for this cleavage mode by HIV-1 and M-MLV RNases H; a 2–3-nucleotide upstream gap permits it. The cited passages do not establish that this mode removes the longer fragments remaining paired to minus DNA. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [52] source
    • cites [53] source
    • cites [54] source

  • May combine two claims.

    Premisecitation

    Thermodynamic studies suggest one Mg2+ at the HIV-1 ribonuclease H active site, while a subset of NMR titration experiments supported two Mg2+ with dissociation constants of about 3 mM and 35 mM.

    “A noteworthy discrepancy in the studies exploring Mg2+ stoichiometry at the HIV-1 RNH active site arises upon comparison of thermodynamic studies that suggest one Mg2+ at the active site [59] and a subset of titration experiments, monitored by NMR, that supported two Mg2+ at the active site (KD, ~ 3 mM and 35 mM) [65,66].”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [59] source
    • cites [65] source

      The ALKALINE PHOSPHATASE section (page not available) says the HIV reverse transcriptase RNase H domain binds two divalent metal ions at its active site. It does not identify them as Mg²⁺ or report NMR titrations or dissociation constants of approximately 3 and 35 mM; it also does not address the thermodynamic finding of one Mg²⁺. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [66] source

  • May combine two claims.

    Premisecitation

    The crystal structure of reverse transcriptase with beta-thujaplicinol showed the inhibitor in the active site chelating two Mn2+ ions and provided insight into the inhibition mechanism.

    “The crystal structure of RT with a hydroxytropolone inhibitor, β-thujaplicinol, showed the inhibitor in the active-site with chelation of two Mn2+ (Figure 5a) and prompted postulation on how RNA/DNA substrate interaction with the inhibitors may occur, providing insight into the mechanism of inhibition [77].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [77] source

      Section 4.3 discusses NMR studies of a different RT inhibitor, BHMP07, and the References list work on hydroxylated tropolones. Searches for β-thujaplicinol and for a crystal structure showing chelation of two Mn2+ ions found no passage in our copy addressing the claimed structure or its proposed inhibition mechanism. (LLM, conf=0.72)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Significant progress has been made in developing active-site ribonuclease H inhibitors.

    “During the past several years, significant progress has been made in the development of active-site RNH inhibitors [32-35].”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [32] source
    • cites [33] source
    • cites [34] source
    • cites [35] source

  • May combine two claims.

    Premisecitation

    Pyrrolyl diketo acids have good potency against integrase and moderate ribonuclease H inhibition, with antiviral EC50 around micromolar, supporting dual integrase-ribonuclease H inhibitor development.

    “Among these derivatives, pyrrolyl diketo acids have shown good potency against IN and moderate inhibition of the RNH, with antiviral EC50 ~μM, demonstrating that identification of dual IN-RNH inhibitors is an attractive strategy for new drug development [83].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [83] source

      The Introduction (page unavailable) lists diketo acids as a class of RNase H inhibitors. But the paper does not identify pyrrolyl diketo acids or report their integrase potency or antiviral EC50; the micromolar antiviral EC50 values in the Results are for manicol analogs. The Discussion favors developing RNase H inhibitors, not specifically dual integrase–RNase H inhibitors. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The polymerase-dependent ribonuclease H cleavage mode occurs during pauses in DNA synthesis and leaves nicks in the RNA as reverse transcriptase slides along it.

    “This mode is polymerase-dependent and occurs during pauses in DNA synthesis, leaving nicks in the RNA as RT slides along it [27,28].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [27] source
    • cites [28] source

      The DNA 3′ end-directed cleavage section reports RNase H cleavage at pause sites during polymerization, and STEP 1 says this mode cleaves the RNA concomitantly with DNA synthesis, presumably at pause sites. These passages support intermittent RNA cleavage, but the paper hedges the timing and does not describe RT sliding along the RNA. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Retroviral reverse transcriptases have three modes of RNA hydrolysis by ribonuclease H: 3'-end DNA-directed cleavage, 5'-end RNA-directed cleavage, and non-directed or internal cleavage.

    “Retroviral RTs, including HIV-1 RT and avian myeloblastosis virus (AMV) RT, which function as heterodimers, as well as M-MLV RT, which functions as a monomer, have three modes of RNA hydrolysis by RNH: 3'-end DNA directed cleavage, 5'-end RNA directed cleavage, and non-directed or internal cleavage [26-28,31,52-54].”
    Quote in the paperNot a substantial claim1 of 7 sources checked
    • cites [26] source
    • cites [27] source
    • cites [28] source
    • cites [31]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [52] source
    • cites [53] source
    • cites [54] source

  • May combine two claims.

    Premisecitation

    The ribonuclease H activity of reverse transcriptase hydrolyzes RNA in RNA/DNA hybrids during DNA synthesis and is critical for virus replication.

    “The RNH activity of RT is responsible for hydrolysis of RNA of RNA/DNA hybrids during synthesis and, thus, is critical for virus replication [3,25-28].”
    Quote in the paperSubstantial claim1 of 5 sources checked
    • cites [3] source
    • cites [25] source
    • cites [26] source
    • cites [27] source
    • cites [28] source

  • May combine two claims.

    Premisecitation

    Crystal structures of reverse transcriptase with N-hydroxy naphthyridinone inhibitors demonstrated direct active-site binding and showed that H539 sterically prevents the inhibitors from flipping to the opposite orientation.

    “Crystal structures of RT with N-hydroxy naphthyridinone inhibitors also experimentally demonstrated direct RNH active-site interaction by the inhibitors and showed that the position of H539 sterically prohibits the naphthyridinones from flipping to an opposite orientation [78] (Figure 5b).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [78] source

      The Introduction and Conclusions discuss Mg²⁺ binding to the HIV-1 RNase H domain, not inhibitor-bound crystal structures. Searches for N-hydroxy naphthyridinones, H539, and inhibitor orientation found no passage addressing the claimed binding or steric restriction; the crystal structures listed in the References do not establish this claim. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Heterodimer formation is essential for both ribonuclease H and polymerase activities of reverse transcriptase, making dimer dissociation a reasonable approach to inhibit both activities.

    “Since heterodimer formation is essential for the RNH activity, as well as the polymerase activity of RT, dimer dissociation is a reasonable approach to inhibit both activities in RT [105,114].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [105] source
    • cites [114] source

  • May combine two claims.

    Premisecitation

    XZ462, but not MK1 or MK2, forms a hydrogen-bonding interaction with the conserved H539 residue.

    “Importantly, XZ462, but not MK1 or MK2, has a hydrogen-bonding interaction with the conserved H539 residue [89].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [89] source

      The Results and Discussion, Molecular modeling section (page unavailable) predicts a potential interaction between compound 13q and conserved H539. Our copy does not identify 13q as XZ462 or discuss MK1 or MK2, so it cannot establish the claimed comparison (searched: XZ462, MK1, MK2, H539). (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    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].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [31] source

      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

  • May combine two claims.

    Premisecitation

    The connection domain interacts with nucleic acids through positively charged side chains, helping heterodimer formation and possibly positioning the substrate in the ribonuclease H active site.

    “the connection domain directly interacts with nucleic acids via positively charged side chains to help heterodimer formation and possibly position the substrate in the RNH active site [14,15].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] source
    • cites [15] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Reverse transcriptase containing a ribonuclease H domain is widely found in retroviruses and long terminal repeat retrotransposons.

    “RNH domain-containing RT has been found widely in both retroviruses and long terminal repeat (LTR) retrotransposons [6].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] source

  • May combine two claims.

    Premisecitation

    The connection domain lacks a catalytic site and has alpha-helices on only one side of its beta-sheet, unlike the ribonuclease H and integrase domains.

    “the connection domain lacks any catalytic site and has α–helices on only one side of the β–sheet (Figure 2a), compared to the RNH and IN domains (Figure 2b and 2c, respectively) [14].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The mature functional form of HIV-1 reverse transcriptase is a heterodimer composed of 66 kDa and 51 kDa subunits.

    “The mature, functional form of HIV-1 RT is a heterodimer, comprising 66 kDa and 51 kDa subunits (Figure 1b)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] source
    • cites [15] source

  • May combine two claims.

    Premisecitation

    A longer substrate interaction site is needed for HIV-1 ribonuclease H activity, as confirmed by restoring activity in a chimeric enzyme with about 20 additional amino acids from E. coli RNase H.

    “The concept that a longer substrate interaction site is needed for HIV-1 RNH domain activity was confirmed by restoration of RNH activity in a chimeric RNH that extends the substrate interaction site by approximately 20 amino acids with a sequence from E. Coli RNH [41].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] source

  • May combine two claims.

    Premisecitation

    Diketo acid, N-hydroxyimide, and hydroxytropolone inhibit integrase strand transfer as well as ribonuclease H.

    “Diketo acid, N-hydroxyimide and hydroxytropolone exhibit INST inhibition as well as RNH inhibition, as explained in a recent review article [34].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] source

  • May combine two claims.

    Premisecitation

    In HIV-1 ribonuclease H, the catalytic acidic residues are D443, E478, D498, and D549, with H539 essential near the active-site pocket.

    “In HIV-1 RNH (Figure 3a), the catalytic acidic residues are D443, E478, D498 and D549 with the essential H539 near the active site pocket (Figure 3b) [51].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] source

  • May combine two claims.

    Premisecitation

    A single substitution mutation in reverse transcriptase significantly lowers dimerization affinity, suggesting that targeting key interface contacts can reduce dimerization.

    “Nevertheless, this approach is supported by the observation that a single substitution mutation in RT significantly lowers the dimerization affinity, suggesting that it is possible to reduce dimerization by targeting key contacts in the interface [107,118-121].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [107] source
    • cites [118] source
    • cites [119] source
    • cites [120] source
    • cites [121] source

  • May combine two claims.

    Premisecitation

    Double-winged inhibitors show high selectivity against integrase strand transfer, with ribonuclease H IC50 below micromolar and antiviral EC50 in the micromolar range.

    “Double-winged inhibitors showed high selectivity against INST inhibition, with RNH IC50 below μM and antiviral EC50 in the μM range [88].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] source
26 of 26

  • The paper relies on this without support.

    No inhibitor targeting the ribonuclease H activity of HIV-1 reverse transcriptase has reached clinical approval or use.

    “Despite the successful development of polymerase-targeting antiviral drugs over the last three decades, no bona fide inhibitor against the RNH activity of HIV-1 RT has progressed to clinical evaluation.”
    “Despite these developments, no FDA-approved inhibitor against the RNH activity of RT is available.”
    “In fact, among the HIV-1 encoded enzyme activities, i.e., protease, polymerase, RNH and integrase, the RNH is the only one for which inhibitors have failed to reach the clinic.”

  • The paper relies on this without support.

    Retroviral ribonuclease H enzymes are validated drug targets.

    “Given that retroviral RNHs are validated but challenging drug targets, such structure and functional studies are likely to aid drug development.”
2 of 2

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Authors
Ilina, T. V., Brosenitsch, T. A., Sluis‐Cremer, N., & Ishima, R.
Affiliations
University of Pittsburgh (US)
Corresponding author
Rieko Ishima
ORCID
Venue
The Enzymes
Publisher
Elsevier
Published
2021
Volume
50
Pages
227-247
ISSN
1874-6047 (ISSN-L)
DOI
10.1016/bs.enz.2021.07.007
PMC
PMC8994160
OpenAlex
W3215912475
Cited by
13
References
127
Citations by year
2026: 3 · 2025: 2 · 2024: 5 · 2023: 2 · 2022: 1
FWCI
8.46
Type
book chapter
Language
en
Open access
Licence
Locations
  • The Enzymes (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • University of Pittsburgh
  • National Institutes of Health (AI150481)
Topics
  • Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
  • Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
Keywords
HIV-1 reverse transcriptase, enzyme structure, catalytic mechanism, antiviral drug design, reverse transcription, DNA polymerase activity
MeSH terms
DNA-Directed DNA Polymerase, HIV-1, Ribonuclease H, Reverse Transcription

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