Regulation of MALAT1 triple helix stability and in vitro degradation by diphenylfurans

被引:40
|
作者
Donlic, Anita [1 ]
Zafferani, Martina [1 ]
Padroni, Giacomo [1 ]
Puri, Malavika [1 ]
Hargrove, Amanda E. [1 ,2 ]
机构
[1] Duke Univ, Dept Chem, 124 Sci Dr, Durham, NC 27708 USA
[2] Duke Univ, Sch Med, Dept Biochem, Durham, NC 27710 USA
基金
美国国家卫生研究院; 美国国家科学基金会;
关键词
LONG NONCODING RNA; SMALL MOLECULES; DNA-BINDING; DESIGN; STABILIZATION; INHIBITION; DERIVATIVES; METASTASIS; DISCOVERY; DOCKING;
D O I
10.1093/nar/gkaa585
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Small molecule-based modulation of a triple helix in the long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been proposed as an attractive avenue for cancer treatment and a model system for understanding small molecule:RNA recognition. To elucidate fundamental recognition principles and structure-function relationships, we designed and synthesized nine novel analogs of a diphenylfuran-based small molecule DPFp8, a previously identified lead binder of MALAT1. We investigated the role of recognition modalities in binding and in silico studies along with the relationship between affinity, stability and in vitro enzymatic degradation of the triple helix. Specifically, molecular docking studies identified patterns driving affinity and selectivity, including limited ligand flexibility, as observed by ligand preorganization and 3D shape complementarity for the binding pocket. The use of differential scanning fluorimetry allowed rapid evaluation of ligand-induced thermal stabilization of the triple helix, which correlated with decreased in vitro degradation of this structure by the RNase R exonuclease. The magnitude of stabilization was related to binding mode and selectivity between the triple helix and its precursor stem loop structure. Together, this work demonstrates the value of scaffold based libraries in revealing recognition principles and of raising broadly applicable strategies, including functional assays, for small molecule-RNA targeting.
引用
收藏
页码:7653 / 7664
页数:12
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