Structure-Guided Discovery of a Novel Aminoglycoside Conjugate Targeting HIV-1 RNA Viral Genome

详细信息    查看全文

• 作者：Eric Ennifar ; Muhammad Waqar Aslam ; Perrine Strasser ; Guillaume Hoffmann ; Philippe Dumas ; Floris L. van Delft
• 刊名：ACS Chemical Biology
• 出版年：2013
• 出版时间：November 15, 2013
• 年：2013
• 卷：8
• 期：11
• 页码：2509-2517
• 全文大小：556K
• 年卷期：v.8,no.11(November 15, 2013)
• ISSN：1554-8937

文摘

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鈥揜NA 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.