title: Inhibition of foamy virus reverse transcriptase by human immunodeficiency virus type 1 RNase H inhibitors.
abstract: 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.
authors.affiliation: University of Cagliari, Department of Life and Environmental Sciences, Cittadella di Monserrato, Monserrato (Cagliari), Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Corona
authors.affiliation: Universität Bayreuth, Lehrstuhl Biopolymere, Bayreuth, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Schneider
authors.affiliation: Universität Bayreuth, Lehrstuhl Biopolymere, Bayreuth, Germany.
authors.forename: Kristian
authors.initials: K
authors.lastname: Schweimer
authors.affiliation: Universität Bayreuth, Lehrstuhl Biopolymere, Bayreuth, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Rösch
authors.affiliation: Universität Bayreuth, Lehrstuhl Biopolymere, Bayreuth, Germany birgitta.woehrl@uni-bayreuth.de tramon@unica.it.
authors.forename: Birgitta M
authors.initials: BM
authors.lastname: Wöhrl
authors.affiliation: University of Cagliari, Department of Life and Environmental Sciences, Cittadella di Monserrato, Monserrato (Cagliari), Italy birgitta.woehrl@uni-bayreuth.de tramon@unica.it.
authors.forename: Enzo
authors.initials: E
authors.lastname: Tramontano
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D002208:Caproates / Q000494:pharmacology; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D062105:Molecular Docking Simulation; D039821:Monoterpenes / Q000494:pharmacology; D019906:Nuclear Magnetic Resonance, Biomolecular; D011758:Pyrroles / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D016914:Ribonuclease H / Q000037:antagonists & inhibitors*; D016092:Spumavirus / Q000201:enzymology*; D014334:Tropolone / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C500206:6-(1-(4-fluorophenyl)methyl-1H-pyrrol-2-yl)-2,4-dioxo-5-hexenoic acid ethyl ester; D019380:Anti-HIV Agents; D002208:Caproates; D039821:Monoterpenes; D011758:Pyrroles; D018894:Reverse Transcriptase Inhibitors; D014334:Tropolone; D054303:HIV Reverse Transcriptase; D016914:Ribonuclease H; C009479:beta-thujaplicin