Ennifar Eric, Aslam Muhammad Waqar, Strasser Perrine, Hoffmann Guillaume, Dumas Philippe, van Delft Floris L
Architecture et Réactivité de l'ARN, Institut de Biologie Moléculaire et Cellulaire, CNRS, Université Louis Pasteur , 15 rue René Descartes, 67084 Strasbourg, France.
ACS Chem Biol. 2013 Nov 15;8(11):2509-17. doi: 10.1021/cb400498n. Epub 2013 Sep 20.
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.
HIV-1基因组RNA的二聚化起始位点（DIS）是一个保守的茎环结构，通过形成环-环复合物促进病毒基因组二聚化。DIS是一个潜在的有趣靶点，因为它对病毒复制的几个关键步骤至关重要。在这项工作中，我们描述了一种合理设计的氨基糖苷缀合物的合成，该缀合物与HIV-1 DIS病毒RNA具有高特异性结合，广泛的体外结合表征表明了这一点。我们提出了一个药物-RNA相互作用的三维模型，该模型与结合数据完美契合。我们的结果表明了靶向HIV DIS病毒RNA二聚体的可行性，并为新型抗病毒药物的合理设计开辟了道路。此外，由于HIV-1 DIS RNA与细菌氨酰基解码位点（A位点）RNA之间存在相似性，我们表明这种新型氨基糖苷缀合物也以与天然氨基糖苷抗生素相似的亲和力结合细菌A位点。
