title: Structure-guided discovery of a novel aminoglycoside conjugate targeting HIV-1 RNA viral genome.
abstract: The dimerization initiation site (DIS) of the HIV-1 genomic RNA is a conserved stem-loop that promotes viral genome dimerization by forming a loop-loop complex. The DIS constitutes a potentially interesting target because it is crucial for several key steps of the viral replication. In this work we describe the synthesis of a rationally designed aminoglycoside conjugate that binds the HIV-1 DIS viral RNA with high specificity, as shown by an extensive in vitro binding characterization. We propose a three-dimensional model of the drug-RNA interaction that perfectly fits with binding data. Our results show the feasibility of targeting the HIV DIS viral RNA dimer and open the way to the rationale design of a new class of antiviral drugs. In addition, due to similarities between the HIV-1 DIS RNA and the bacterial aminoacyl decoding site (A site) RNA, we show that this novel aminoglycoside conjugate also binds the bacterial A site with a similar affinity as natural aminoglycoside antibiotics.
authors.affiliation: Architecture et Réactivité de l'ARN, Institut de Biologie Moléculaire et Cellulaire, CNRS, Université Louis Pasteur , 15 rue René Descartes, 67084 Strasbourg, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Ennifar
authors.forename: Muhammad Waqar
authors.initials: MW
authors.lastname: Aslam
authors.forename: Perrine
authors.initials: P
authors.lastname: Strasser
authors.forename: Guillaume
authors.initials: G
authors.lastname: Hoffmann
authors.forename: Philippe
authors.initials: P
authors.lastname: Dumas
authors.forename: Floris L
authors.initials: FL
authors.lastname: van Delft
mesh_terms: D000617:Aminoglycosides / Q000737:chemistry* / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology; D016503:Drug Delivery Systems; D016679:Genome, Viral; D006001:Glycoconjugates / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D012367:RNA, Viral / Q000737:chemistry*
chemical_list: D000617:Aminoglycosides; D019380:Anti-HIV Agents; D006001:Glycoconjugates; D012367:RNA, Viral