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一种基于环和包含AGO的虚拟筛选模型，靶向AGO介导的miRNA-mRNA相互作用用于药物发现，以挽救基因修饰小鼠的骨骼表型。

A Loop-Based and AGO-Incorporated Virtual Screening Model Targeting AGO-Mediated miRNA-mRNA Interactions for Drug Discovery to Rescue Bone Phenotype in Genetically Modified Mice.

作者信息

Zhuo Zhenjian, Wan Youyang, Guan Daogang, Ni Shuaijian, Wang Luyao, Zhang Zongkang, Liu Jin, Liang Chao, Yu Yuanyuan, Lu Aiping, Zhang Ge, Zhang Bao-Ting

机构信息

School of Chinese Medicine Faculty of Medicine The Chinese University of Hong Kong Hong Kong SAR China.

Aptacure Therapeutics Limited Kowloon Hong Kong SAR China.

出版信息

Adv Sci (Weinh). 2020 May 28;7(13):1903451. doi: 10.1002/advs.201903451. eCollection 2020 Jul.

DOI:10.1002/advs.201903451
PMID:32670749
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7341099/
Abstract

Several virtual screening models are proposed to screen small molecules only targeting primary miRNAs without selectivity. Few attempts have been made to develop virtual screening strategies for discovering small molecules targeting mature miRNAs. Mature miRNAs and their specific target mRNA can form unique functional loops during argonaute (AGO)-mediated miRNA-mRNA interactions, which may serve as potential targets for small-molecule drug discovery. Thus, a loop-based and AGO-incorporated virtual screening model is constructed for targeting the loops. The previously published studies have found that miR-214 can target ATF4 to inhibit osteoblastic bone formation, whereas miR-214 can target TRAF3 to promote osteoclast activity. By using the virtual model, the top ten candidate small molecules targeting miR-214-ATF4 mRNA interactions and top ten candidate small molecules targeting miR-214-TRAF3 mRNA interactions are selected, respectively. Based on both in vitro and in vivo data, one small molecule can target miR-214-ATF4 mRNA to promote ATF4 protein expression and enhance osteogenic potential, whereas one small molecule can target miR-214-TRAF3 mRNA to promote TRAF3 protein expression and inhibit osteoclast activity. These data indicate that the loop-based and AGO-incorporated virtual screening model can help to obtain small molecules specifically targeting miRNA-mRNA interactions to rescue bone phenotype in genetically modified mice.

摘要

提出了几种虚拟筛选模型来筛选仅靶向初级微小RNA而无选择性的小分子。很少有人尝试开发用于发现靶向成熟微小RNA的小分子的虚拟筛选策略。成熟微小RNA及其特定的靶mRNA在AGO介导的微小RNA-mRNA相互作用过程中可形成独特的功能环，这可能成为小分子药物发现的潜在靶点。因此，构建了一种基于环且包含AGO的虚拟筛选模型来靶向这些环。先前发表的研究发现，miR-214可靶向ATF4以抑制成骨细胞的骨形成，而miR-214可靶向TRAF3以促进破骨细胞活性。通过使用该虚拟模型，分别选择了靶向miR-214-ATF4 mRNA相互作用的前十个候选小分子和靶向miR-214-TRAF3 mRNA相互作用的前十个候选小分子。基于体外和体内数据，一种小分子可靶向miR-214-ATF4 mRNA以促进ATF4蛋白表达并增强成骨潜能，而一种小分子可靶向miR-214-TRAF3 mRNA以促进TRAF3蛋白表达并抑制破骨细胞活性。这些数据表明，基于环且包含AGO的虚拟筛选模型有助于获得特异性靶向微小RNA-mRNA相互作用的小分子，以挽救基因修饰小鼠的骨表型。

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