ncRNA: structure, function and inhibition

用具有药理学特性的小分子靶向RNA 成功的药物将打开一个尚未开发的药物靶点领域 在mRNA和ncRNA中。然而，成功发现有效的和细胞活性的 RNA抑制剂需要对RNA识别的基本理解， 分子。这方面的知识在很大程度上是缺失的，因为很少有例子 （<10）在与RNA有效结合的小分子的学术和专利文献中， (nM)特别是具有类似药物的化学性质。 在MIRA项目的前4年，我们发现了一类药物- 比如以纳摩尔的亲和力和特异性与几种RNA结合的分子。 这一突破开启了一个特殊的机会， RNA识别的基本原理广泛的影响和意义 除了22篇学术出版物和2项专利外，这项发现还得到了 分拆，许可在肿瘤学中使用化学物质，由照明设备审查 药物化学家，与4个重磅炸弹药物的开发一起归功于。 这种延续的前提是， 这些药物样小分子对RNA的分子识别原理， 导致有效结合的结构、化学、能量和动力学性质， 特异性，将使我们能够确定额外的特权支架的RNA， 发现致病RNA病毒复制的有效抑制剂。 为了实现这一目标，我们将通过3D解剖RNA-小分子识别 结构测定和化学，热力学和 绑定的动态。我们还将开发我们发现的化学物质， 在应对登革热和寨卡病毒感染方面尚未满足的临床需求， 迄今为止，疫苗接种并不成功。我们将与传染病合作 生物学家在细胞和模型生物中进行实验，以检查抗- 在生物学上有意义的情况下的病毒活性，并证明细胞RNA 订婚

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.