A small molecule, Lys-Ala-7-amido-4-methylcoumarin, facilitates RNA dimer maturation of a stem-loop 1 transcript in vitro: structure-activity relationship of the activator.
A small molecule, Lys-Ala-7-amido-4-methylcoumarin, facilitates RNA dimer maturation of a stem-loop 1 transcript in vitro: structure-activity relationship of the activator.
复制标题
小分子 Lys-Ala-7-amido-4-methylcoumarin 在体外促进茎环 1 转录本的 RNA 二聚体成熟：激活剂的结构-活性关系。
DOI：
10.1021/bi800230m
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发表时间：
2008
期刊：
影响因子：
2.9
通讯作者：
James,ThomasL
中科院分区：
文献类型：
--
作者：
Chung,Janet;Mujeeb,Anwer;Jiang,Yongying;Guilbert,Christophe;Pendke,Mrunal;Wu,Yanfen;James,ThomasL
The type 1 human immunodeficiency virus (HIV-1), like all retroviruses, contains two copies of the RNA genome as a dimer. A dimer initially forms via a self-complementary sequence in the dimer initiation site (DIS) of the genomic RNA, but that dimer is converted to a mature dimer in a process generally promoted by the viral nucleocapsid (NC) protein. Formation of the mature dimer is correlated with infectivity. Study of genomic dimerization has been facilitated by discovery of short RNA transcripts containing the DIS stem−loop 1 (SL1), which can dimerize spontaneously without any protein factors in vitro as well as via the NC protein. On the basis of the palindromic nature of the apical loop of SL1, a kissing loop model has been proposed. First, a metastable kissing dimer is formed via a loop−loop interaction and then converted into a more stable extended dimer by the NC protein. This dimerization process in vitro is believed to mimic the in vivo RNA maturation. During experimental screening of potential inhibitors, we discovered a small molecule, Lys-Ala-7-amido-4-methylcoumarin (KA-AMC), which facilitates the in vitro conversion from kissing dimer to extended dimer. Here we report the structure−activity relationship for KA-AMC for promoting dimer maturation. Guanidino groups and increasing positive charge on the side chain enhance activity. For activity, the charged side chain is preferred on the benzene ring, and O1in the coumarin scaffold is essential. NMR studies show that the coumarin derivatives stack with aromatic bases of the RNA. The coumarin derivatives may aid in the investigation of some aspects of dimer maturation and serve as a scaffold for design of maturation inhibitors or of activators of premature maturation, either of which can lead to a potential HIV therapeutic.
