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DOI | 10.1073/PNAS.2012217117 |
A general fragment-based approach to identify and optimize bioactive ligands targeting RNA | |
Suresh B.M.; Li W.; Zhang P.; Wang K.W.; Yildirim I.; Parker C.G.; Disney M.D. | |
发表日期 | 2021 |
ISSN | 00278424 |
起始页码 | 33197 |
结束页码 | 33203 |
卷号 | 117期号:52 |
英文摘要 | RNAs have important functions that are dictated by their structure. Indeed, small molecules that interact with RNA structures can perturb function, serving as chemical probes and lead medicines. Here we describe the development of a fragment-based approach to discover and optimize bioactive small molecules targeting RNA. We extended the target validation method chemical cross-linking and isolation by pull-down (Chem-CLIP) to identify and map the binding sites of low molecular weight fragments that engage RNA or Chem-CLIP fragment mapping (Chem-CLIP-Frag-Map). Using Chem-CLIP-Frag-Map, we identified several fragments that bind the precursor to oncogenic microRNA-21 (pre-miR-21). Assembly of these fragments provided a specific bioactive compound with improved potency that inhibits pre-miR-21 processing, reducing mature miR-21 levels. The compound exerted selective effects on the transcriptome and selectively mitigated a miR-21–associated invasive phenotype in triple-negative breast cancer cells. The Chem-CLIP-Frag-Map approach should prove general to expedite the identification and optimization of small molecules that bind RNA targets. © 2020 National Academy of Sciences. All rights reserved. |
英文关键词 | Chemical biology | cancer; Fragment-based drug discovery; Nucleic acids; RNA |
语种 | 英语 |
scopus关键词 | antineoplastic agent; ligand; microRNA; MIRN21 microRNA, human; cell line; chemistry; drug development; female; human; metabolism; molecular docking; molecular library; nucleotide motif; pharmacology; procedures; triple negative breast cancer; tumor cell line; Antineoplastic Agents; Cell Line; Cell Line, Tumor; Drug Discovery; Female; Humans; Ligands; MicroRNAs; Molecular Docking Simulation; Nucleotide Motifs; Small Molecule Libraries; Triple Negative Breast Neoplasms |
来源期刊 | Proceedings of the National Academy of Sciences of the United States of America
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文献类型 | 期刊论文 |
条目标识符 | http://gcip.llas.ac.cn/handle/2XKMVOVA/179634 |
作者单位 | Department of Chemistry, Scripps Research Institute, Jupiter, FL 33458, United States; Department of Chemistry and Biochemistry, Florida Atlantic University, Jupiter, FL 33458, United States |
推荐引用方式 GB/T 7714 | Suresh B.M.,Li W.,Zhang P.,et al. A general fragment-based approach to identify and optimize bioactive ligands targeting RNA[J],2021,117(52). |
APA | Suresh B.M..,Li W..,Zhang P..,Wang K.W..,Yildirim I..,...&Disney M.D..(2021).A general fragment-based approach to identify and optimize bioactive ligands targeting RNA.Proceedings of the National Academy of Sciences of the United States of America,117(52). |
MLA | Suresh B.M.,et al."A general fragment-based approach to identify and optimize bioactive ligands targeting RNA".Proceedings of the National Academy of Sciences of the United States of America 117.52(2021). |
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