title: Inhibition of HIV-1 ribonuclease H activity by novel frangula-emodine derivatives.
abstract: The HIV-1 reverse transcriptase (RT) associated ribonuclease H (RNase H) activity hydrolyzes the RNA component of the viral heteroduplex RNA:DNA replication intermediate. Even though this function is essential for viral replication, until now only very few compounds have been reported to inhibit it. Anthraquinones are common secondary metabolites which have diverse biological activities. In particular, some of them have been reported to inhibit the HIV-1 RT polymerase and integrase activities in biochemical assays. Given the structural similarities between integrase and RNase H proteins, we synthesized a series of frangula-emodine derivatives and showed that the introduction of a bromine atom in position 7 of the anthraquinone structure leads to derivatives which are able to inhibit both HIV-1 polymerase and RNase H functions at micromolar concentrations. Mechanism of action studies performed on the 7-brom-6-capital O, Cyrillic-phenacyl-1,8-dihydroxy-3-methyl anthraquinone (K67) showed that this compound is a non-competitive inhibitor of the RNase H function and that it binds to a site which is not overlapping to the non-nucleoside RT inhibitors binding site. This study demonstrates that anthraquinone derivatives may be a scaffold to be further developed to obtain selective HIV-1 RNase H inhibitors and represent a new step toward the identification of new anti-RT agents.
authors.affiliation: A.B. Bekturov Institute of Chemical Sciences, 050010, Almaty, Kazakhstan.
authors.forename: Kharlamova
authors.initials: K
authors.lastname: Tatyana
authors.forename: Esposito
authors.initials: E
authors.lastname: Francesca
authors.forename: Zinzula
authors.initials: Z
authors.lastname: Luca
authors.forename: Floris
authors.initials: F
authors.lastname: Giovanni
authors.forename: Yung-Chi
authors.initials: YC
authors.lastname: Cheng
authors.forename: E Dutschman
authors.initials: ED
authors.lastname: Ginger
authors.forename: Tramontano
authors.initials: T
authors.lastname: Enzo
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004347:Drug Interactions; D004642:Emodin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000378:metabolism; D015497:HIV-1 / Q000201:enzymology*; D007700:Kinetics; D019829:Nevirapine / Q000737:chemistry; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry; D016914:Ribonuclease H / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D018894:Reverse Transcriptase Inhibitors; D004247:DNA; D019829:Nevirapine; D054303:HIV Reverse Transcriptase; D016914:Ribonuclease H; D004642:Emodin