title: Aptamer displacement identifies alternative small-molecule target sites that escape viral resistance.
abstract: Aptamers targeting reverse transcriptase (RT) from HIV-1 inhibit viral replication in vitro, presumably by competing with binding of the primer/template complex. This site is not targeted by the currently available small-molecule anti-HIV-1 RT inhibitors. We have identified SY-3E4, a small-molecule inhibitor of HIV-1 RT, by applying a screening assay that utilizes a reporter-ribozyme regulated by the anti-HIV-1 RT aptamer. SY-3E4 displaces the aptamer from the protein, selectively inhibits DNA-dependent, but not RNA-dependent, polymerase activity, and inhibits the replication of both the wild-type virus and a multidrug-resistant strain. Analysis of available structural data of HIV-1 and HIV-2 RTs rationalizes many of the observed characteristics of the inhibitory profiles of SY-3E4 and the aptamer and suggests a previously not considered region in these RTs as a target for antiviral therapy. Our study reveals unexplored ways for rapidly identifying alternative small-molecule target sites in proteins and illustrates strategies for overcoming resistance-conferring mutations with small molecules.
authors.affiliation: LIMES Program Unit Chemical Biology & Medicinal Chemistry, c/o Kekulé Institute for Organic Chemistry & Biochemistry, University of Bonn, Gerhard-Domagk-Strasse 1, D-53121 Bonn, Germany.
authors.forename: Satoko
authors.initials: S
authors.lastname: Yamazaki
authors.forename: Lu
authors.initials: L
authors.lastname: Tan
authors.forename: Günter
authors.initials: G
authors.lastname: Mayer
authors.forename: Jörg S
authors.initials: JS
authors.lastname: Hartig
authors.forename: Jin-Na
authors.initials: JN
authors.lastname: Song
authors.forename: Sandra
authors.initials: S
authors.lastname: Reuter
authors.forename: Tobias
authors.initials: T
authors.lastname: Restle
authors.forename: Sandra D
authors.initials: SD
authors.lastname: Laufer
authors.forename: Dina
authors.initials: D
authors.lastname: Grohmann
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Kräusslich
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bajorath
authors.forename: Michael
authors.initials: M
authors.lastname: Famulok
mesh_terms: D052157:Aptamers, Nucleotide; D002460:Cell Line; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000737:chemistry / Q000235:genetics; D015497:HIV-1 / Q000201:enzymology / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D014779:Virus Replication
chemical_list: D052157:Aptamers, Nucleotide; D054303:HIV Reverse Transcriptase