ncRNA: structure, function and inhibition

ncRNA：结构、功能和抑制

• 批准号: 10621500
• 负责人: Gabriele Varani
• 金额: $ 69.88万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621500
• 关键词: Address; Affinity; Binding; Biophysics; Cells; Chemicals; Chemistry; Clinical; Collaborations; Communicable Diseases; Dengue Infection; Dengue Virus; Development; Goals; Investigation; Knowledge; Legal patent; Licensing; Literature; Medicine; Messenger RNA; Oncology; Pathogenicity; Pharmaceutical Preparations; Pharmacologic Substance; Property; Publications; RNA; RNA Viruses; Small RNA; Specificity; Structure; Thermodynamics; Vaccination; Viral Physiology; Zika Virus; drug candidate; drug-like compound; experimental study; human disease; inhibitor; model organism; molecular recognition; nanomolar; pharmacologic; scaffold; small molecule; success; three dimensional structure

Targeting RNA with small molecules with the pharmacological properties of successful drugs would open-up an untapped universe of pharmaceutical targets within mRNAs and ncRNAs. However, the successful discovery of potent and cell-active inhibitors of RNA requires a fundamental understanding of RNA recognition by small molecules. This knowledge is largely missing, because there are very few examples (<10) in the academic and patent literature of small molecules that bind to RNA potently (nM) and specifically and that also possess drug-like chemistry. In the first 4 years of this MIRA project, we have discovered a class of drug- like molecules that bind to several RNAs with nanomolar affinity and specificity. This breakthrough opens-up an exceptional opportunity to investigate the fundamental principles of RNA recognition. The very broad impact and significance of the discovery is validated, in addition to 22 academic publications and 2 patents, by a spin-off which licensed the use of the chemistry in oncology, vetted by luminaire medicinal chemists, credited together with the development of 4 blockbuster drugs. The premise of this continuation is that a fundamental understanding of the principles of molecular recognition of RNA by these drug-like small molecules, of the structural, chemical, energetic and dynamic properties that lead to potent binding and specificity, would allow us to identify additional privileged scaffolds for RNA, and to discover potent inhibitors of replication of pathogenic RNA viruses. To achieve this goal, we will dissect RNA-small molecule recognition through 3D structure determination and investigations of the chemistry, thermodynamics and dynamics of binding. We will also develop the chemistry we have discovered to address unmet clinical needs in addressing infections by Dengue and Zika viruses, where vaccination has so far been unsuccessful. We will collaborate with infectious disease biologists to conduct experiments in cells and model organisms to examine anti- viral activity in biologically meaningful contexts and demonstrate cellular RNA engagement.

以小分子靶向RNA的药理学特性 成功的药物将打开一个未被开发的药物靶标宇宙 在mRNAs和ncRNA中。然而，强效和细胞活性的成功发现 RNA抑制剂需要对小分子RNA识别有基本的了解 分子。这种知识在很大程度上是缺失的，因为很少有例子 (&lt；10)在与RNA有效结合的小分子的学术和专利文献中 (NM)，具体地说，它还具有类药物化学。 在这个Mira项目的头4年里，我们发现了一类药物- 类似于与几个具有纳摩尔亲和力和特异性的RNA结合的分子。 这一突破打开了一个特殊的机会，调查 RNA识别的基本原理。非常广泛的影响和意义 除了22篇学术出版物和2项专利外，这一发现还得到了 分拆公司，获得在肿瘤学中使用化学物质的许可，由LIGHTILER审查 药物化学家，与4种重磅炸弹药物的开发相提并论。 这种延续的前提是，对 这些类药物小分子对RNA的分子识别原理 结构、化学、能量和动力学性质，导致强有力的结合和 特异性，将使我们能够识别更多的RNA特权支架，并 发现致病核糖核酸病毒复制的有效抑制剂。 为了实现这一目标，我们将通过3D对RNA-小分子识别进行剖析 结构测定及化学、热力学和核磁共振研究 捆绑的动力学。我们还将发展我们已经发现要解决的化学问题 在应对登革热和寨卡病毒感染方面未得到满足的临床需求， 到目前为止，疫苗接种还没有成功。我们将与传染病合作 生物学家将在细胞和模型生物中进行实验，以检查抗病毒 病毒在具有生物学意义的背景下的活性并展示细胞RNA 订婚。

项目成果

Design of RNA-targeting macrocyclic peptides.

RNA 靶向大环肽的设计。

• DOI: 10.1016/bs.mie.2019.04.029
• 发表时间: 2019
• 期刊: Methods in enzymology
• 作者: Walker,MatthewJ;Varani,Gabriele
• 通讯作者: Varani,Gabriele

A Slow Dynamic RNA Switch Regulates Processing of microRNA-21.

• DOI: 10.1016/j.jmb.2022.167694
• 发表时间: 2022-08-30
• 期刊: JOURNAL OF MOLECULAR BIOLOGY
• 影响因子: 5.6
• 作者: Shortridge, Matthew D.;Olsen, Greg L.;Yang, Wen;Walker, Matthew J.;Varani, Gabriele
• 通讯作者: Varani, Gabriele

Molecular basis for the increased affinity of an RNA recognition motif with re-engineered specificity: A molecular dynamics and enhanced sampling simulations study

• DOI: 10.1371/journal.pcbi.1006642
• 发表时间: 2018-12-01
• 期刊: PLOS COMPUTATIONAL BIOLOGY
• 影响因子: 4.3
• 作者: Bochicchio, Anna;Krepl, Miroslav;Carloni, Paolo
• 通讯作者: Carloni, Paolo

Two distinct binding modes provide the RNA-binding protein RbFox with extraordinary sequence specificity.

两种不同的结合模式为 RNA 结合蛋白 RbFox 提供了非凡的序列特异性

• DOI: 10.1038/s41467-023-36394-3
• 发表时间: 2023-02-09
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Ye, Xuan;Yang, Wen;Yi, Soon;Zhao, Yanan;Varani, Gabriele;Jankowsky, Eckhard;Yang, Fan
• 通讯作者: Yang, Fan

NMR structure of Dengue West Nile viruses stem-loop B: A key cis-acting element for flavivirus replication.

• DOI: 10.1016/j.bbrc.2020.07.115
• 发表时间: 2020-08
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Shrikant Sharma;G. Varani