Ligands with polyfluorophenyl moieties promote a local structural rearrangement in the Spinach2 and Broccoli aptamers that increases ligand affinities.
Ligands with polyfluorophenyl moieties promote a local structural rearrangement in the Spinach2 and Broccoli aptamers that increases ligand affinities.
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DOI：
10.1261/rna.079005.121
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发表时间：
2022-06
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核酸与其分子靶标的相互作用通常涉及结构重组，可能跨越复杂的折叠景观。随着最近认识到许多rna，包括编码rna和非编码rna，可能通过与靶分子相互作用来调节细胞活动，了解核酸如何与它们的靶分子相互作用以及如何开发影响关键折叠转变的药物变得越来越重要。我们广泛研究了Spinach2和西兰花适配体与DFHBI [(Z)-5-（3,5-二氟-4-羟基苄基）-2,3-二甲基-3,5-二氢- 4h -咪唑-4-one]的不同延伸修饰的小分子配体库的相互作用，这些配体从Spinach2配体结合口袋伸出。对这些化合物与适配体相互作用的研究表明，多氟苯基修饰配体引发适配体亲和力的缓慢变化，需要较长的时间（半衰期约40分钟）才能实现。亲和性的变化似乎涉及到进入配体结合袋的初始破坏，随后逐渐过渡到更明确的结构，其中最可能的驱动力是入口腺嘌呤与附近的2'OH基团的相互作用。这些结果表明，多氟苯基修饰可能会增加小分子药物破坏局部结构和促进RNA重塑的能力。
The interaction of nucleic acids with their molecular targets often involves structural reorganization that may traverse a complex folding landscape. With the more recent recognition that many RNAs, both coding and noncoding, may regulate cellular activities by interacting with target molecules, it becomes increasingly important to understand how nucleic acids interact with their targets and how drugs might be developed that can influence critical folding transitions. We have extensively investigated the interaction of the Spinach2 and Broccoli aptamers with a library of small molecule ligands modified by various extensions from the imido nitrogen of DFHBI [(Z)-5-(3,5-difluoro-4-hydroxybenzylidene)-2,3-dimethyl-3,5-dihydro-4H-imidazol-4-one] that reach out from the Spinach2 ligand binding pocket. Studies of the interaction of these compounds with the aptamers revealed that polyfluorophenyl-modified ligands initiate a slow change in aptamer affinity that takes an extended time (half-life of ∼40 min) to achieve. The change in affinity appears to involve an initial disruption of the entrance to the ligand binding pocket followed by a gradual transition to a more defined structure for which the most likely driving force is an interaction of the gateway adenine with a nearby 2′OH group. These results suggest that polyfluorophenyl modifications might increase the ability of small molecule drugs to disrupt local structure and promote RNA remodeling.
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DOI：
10.1126/science.1207339
发表时间：
2011-07-29
期刊：
Science (New York, N.Y.)
影响因子：
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影响因子：
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DOI：
10.1007/978-94-007-5561-1_4
发表时间：
2013-01-01
期刊：
METALLOMICS AND THE CELL
影响因子：
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作者：
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