Re-Engineering RNA Molecules into Therapeutic Agents.

Abstract:
Efforts to chemically modify nucleic acids got underway merely a decade after the discovery of the DNA double helix and initially targeted nucleosides and nucleotides. The origins of three analogues that remain staples of modification strategies and figure prominently in FDA-approved nucleic acid therapeutics can be traced to the 1960s: 2 -deoxy-2 -fluoro-RNA (2 -F RNA), 2 - O-methyl-RNA (2 - OMe RNA), and the phosphorothioates (PS-DNA/RNA). Progress in nucleoside phosphoramidite-based solid phase oligonucleotide synthesis has gone hand in hand with the creation of second-generation (e.g., 2 - O-(2-methoxyethyl)-RNA, MOE-RNA) and third-generation (e.g., bicyclic nucleic acids, BNAs) analogues, giving rise to an expanding universe of modified nucleic acids. Thus, beyond site-specifically altered DNAs and RNAs with a modified base, sugar, and/or phosphate backbone moieties, nucleic acid chemists have created a host of conjugated oligonucleotides and artificial genetic polymers (XNAs). The search for oligonucleotides with therapeutic efficacy constitutes a significant driving force for these investigations. However, nanotechnology, diagnostics, synthetic biology and genetics, nucleic acid etiology, and basic research directed at the properties of native and artificial pairing systems have all stimulated the design of ever more diverse modifications. Modification of nucleic acids can affect pairing and chemical stability, conformation and interactions with a flurry of proteins and enzymes that play important roles in uptake, transport or processing of targets. Enhancement of metabolic stability is a central concern in the design of antisense, siRNA and aptamer oligonucleotides for therapeutic applications. In the antisense approach, uniformly modified oligonucleotides or so-called gapmers are used to target a specific RNA. The former may sterically block transcription or direct alternative splicing, whereas the latter feature a central PS window that elicits RNase H-mediated cleavage of the target. The key enzyme in RNA interference (RNAi) is Argonaute 2 (Ago2), a dynamic multidomain enzyme that binds multiple regions of the guide (antisense) and passenger (sense) siRNAs. The complexity of the individual interactions between Ago2 and the siRNA duplex provides significant challenges for chemical modification. Therefore, a uniform (the same modification throughout, e.g., antisense) or nearly uniform (e.g., aptamer) modification strategy is less useful in the pursuit of siRNA therapeutic leads. Instead, unique structural features and protein interactions of 5 -end (guide/Ago2MID domain), seed region, central region (cleavage site/Ago2 PIWI domain), and 3 -terminal nucleotides (guide/Ago2 PAZ domain) demand a more nuanced approach in the design of chemically modified siRNAs for therapeutic use. This Account summarizes current siRNA modification strategies with an emphasis on the regio-specific interactions between oligonucleotide and Ago2 and how these affect the choice of modification and optimization of siRNA efficacy. In addition to standard assays applied to measure the effects of modification on the stability of pairing and resistance against nuclease degradation, structural insights based on crystallographic data for modified RNAs alone and in complex with Ago2 from molecular modeling studies are a valuable guide in the design of siRNA therapeutics. Thus, this comprehensive approach is expected to result in accelerated generation of new siRNA-based therapies against various diseases, now that the first siRNA has obtained approval by the US FDA for treatment of hereditary hATTR amyloidosis.
Author Listing： Martin Egli;Muthiah Manoharan
Volume： 52 4
Pages： \n 1036-1047\n
DOI： 10.1021/acs.accounts.8b00650
Language： English
Journal： Accounts of chemical research

ACCOUNTS OF CHEMICAL RESEARCH

Acc. Chem. Res.

影响因子：16.4 是否综述期刊：是 是否OA：否 是否预警：不在预警名单内 发行时间：1968 ISSN：0001-4842 发刊频率：Monthly 收录数据库：SCIE/Scopus收录 出版国家/地区：UNITED STATES 出版社：American Chemical Society

期刊介绍

Accounts of Chemical Research 主要发表化学和生物化学领域内关于基础研究和应用的短小精悍、具有作者团队自己研究特色的述评文章，或者前瞻性观点。这些短综述都是基于作者自己实验室的过往研究，以便向读者完整介绍研究项目。期刊收录研究方向：化学，化学综合Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Visit the Accounts Special Issues page for listings, descriptions, and TOC's of all special issues.Beginning in 2008, Accounts of Chemical Research replaced their traditional article abstract with an article "Conspectus." These new entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article’s discoverability by search engines and the exposure for the research.

化学研究报告提供了简短，简洁和关键的文章，提供了化学和生物化学所有领域的基础研究和应用的易于阅读的概述。此外，《化学研究报告》还出版了专门针对异常活动和意义的单一问题的特刊。访问帐户特殊问题页面以获取所有特殊问题的列表，描述和目录。从2008年开始，化学研究帐户用文章 “Conspectus” 代替了传统的文章摘要。这些新条目概述了这项研究，使读者可以更仔细地了解文章的内容和意义。通过提供对文章内容的更详细描述，Conspectus增强了搜索引擎对文章的可发现性和对研究的了解。

年发文量 311
国人发稿量 102
国人发文占比 32.8%
自引率 0.6%
平均录取率 极难
平均审稿周期 一般,3-6周
版面费 -
偏重研究方向 化学-化学综合
期刊官网 https://pubs.acs.org/journal/achre4
投稿链接 https://acs.manuscriptcentral.com/acs

质量指标占比

研究类文章占比 OA被引用占比 撤稿占比 出版后修正文章占比
0.00% 12.32% 0.00% 0.90%

相关指数

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期刊预警不是论文评价，更不是否定预警期刊发表的每项成果。《国际期刊预警名单（试行）》旨在提醒科研人员审慎选择成果发表平台、提示出版机构强化期刊质量管理。

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分区表升级版（试行）旨在解决期刊学科体系划分与学科发展以及融合趋势的不相容问题。由于学科交叉在当代科研活动的趋势愈发显著，学科体系构建容易引发争议。为了打破学科体系给期刊评价带来的桎梏，“升级版方案”首先构建了论文层级的主题体系，然后分别计算每篇论文在所属主题的影响力，最后汇总各期刊每篇论文分值，得到“期刊超越指数”，作为分区依据。

分区表升级版（试行）的优势：一是论文层级的主题体系既能体现学科交叉特点，又可以精准揭示期刊载文的多学科性；二是采用“期刊超越指数”替代影响因子指标，解决了影响因子数学性质缺陷对评价结果的干扰。整体而言，分区表升级版（试行）突破了期刊评价中学科体系构建、评价指标选择等瓶颈问题，能够更为全面地揭示学术期刊的影响力，为科研评价“去四唯”提供解决思路。相关研究成果经过国际同行的认可，已经发表在科学计量学领域国际重要期刊。

《2019年中国科学院文献情报中心期刊分区表升级版（试行）》首次将社会科学引文数据库（SSCI）期刊纳入到分区评估中。升级版分区表（试行）设置了包括自然科学和社会科学在内的18个大类学科。基础版和升级版（试行）将过渡共存三年时间，推测在此期间各大高校和科研院所仍可能会以基础版为考核参考标准。 提示：中科院分区官方微信公众号“fenqubiao”仅提供基础版数据查询，暂无升级版数据，请注意区分。

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