Inhibition of foamy virus reverse transcriptase by human immunodeficiency virus type 1 RNase H inhibitors

Antimicrob Agents Chemother. 2014 Jul;58(7):4086-93. doi: 10.1128/AAC.00056-14. Epub 2014 May 5.


RNase H plays an essential role in the replication of human immunodeficiency virus type 1 (HIV-1). Therefore, it is a promising target for drug development. However, the identification of HIV-1 RNase H inhibitors (RHIs) has been hampered by the open morphology of its active site, the limited number of available RNase H crystal structures in complex with inhibitors, and the fact that, due to the high concentrations of Mg(2+) needed for protein stability, HIV-1 RNase H is not suitable for nuclear magnetic resonance (NMR) inhibitor studies. We recently showed that the RNase H domains of HIV-1 and prototype foamy virus (PFV) reverse transcriptases (RTs) exhibit a high degree of structural similarity. Thus, we examined whether PFV RNase H can serve as an HIV-1 RNase H model for inhibitor interaction studies. Five HIV-1 RHIs inhibited PFV RNase H activity at low-micromolar concentrations similar to those of HIV-1 RNase H, suggesting pocket similarity of the RNase H domains. NMR titration experiments with the PFV RNase H domain and the RHI RDS1643 (6-[1-(4-fluorophenyl)methyl-1H-pyrrol-2-yl)]-2,4-dioxo-5-hexenoic acid ethyl ester) were performed to determine its binding site. Based on these results and previous data, in silico docking analysis showed a putative RDS1643 binding region that reaches into the PFV RNase H active site. Structural overlays were performed with HIV-1 and PFV RNase H to propose the RDS1643 binding site in HIV-1 RNase H. Our results suggest that this approach can be used to establish PFV RNase H as a model system for HIV-1 RNase H in order to identify putative inhibitor binding sites in HIV-1 RNase H.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / pharmacology*
  • Caproates / pharmacology
  • Catalytic Domain
  • Crystallography, X-Ray
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV-1 / drug effects
  • Humans
  • Molecular Docking Simulation
  • Monoterpenes / pharmacology
  • Nuclear Magnetic Resonance, Biomolecular
  • Pyrroles / pharmacology
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Ribonuclease H / antagonists & inhibitors*
  • Spumavirus / enzymology*
  • Tropolone / analogs & derivatives
  • Tropolone / pharmacology


  • 6-(1-(4-fluorophenyl)methyl-1H-pyrrol-2-yl)-2,4-dioxo-5-hexenoic acid ethyl ester
  • Anti-HIV Agents
  • Caproates
  • Monoterpenes
  • Pyrroles
  • Reverse Transcriptase Inhibitors
  • Tropolone
  • HIV Reverse Transcriptase
  • Ribonuclease H
  • beta-thujaplicin