气候变化领域集成服务门户(CCPortal): A general fragment-based approach to identify and optimize bioactive ligands targeting RNA

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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
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).