This award is being made through the Chemistry of Life Processes (CLP) Program of the Chemistry Division, the Genetic Mechanisms Cluster of the Division of Molecular and Cellular Biosciences, and the Computational and Data-Enabled Science and Engineering (CDS&E) Program at NSF. The central role of ribonucleic acids (RNAs) in biology has long been recognized, but the large number of “non-coding” structured RNA molecules in cells and their diverse functions have only come to light over the past decade. The goal of this project is to identify a collection of chemical compounds that bind with high selectivity and affinity to small elements of unusual structure found in RNA molecules. To this end, solution NMR spectroscopy and computational methods have been employed to identify and characterize compounds that bind a selection of structure elements present in RNA molecules essential to cell functions. The active compounds will be leveraged as new tools for biotechnological and biochemical research and have the high potential for applications in medicine. Education and advancement of scientific discovery with the availability of new molecular tools have benefited from this project. In addition to graduate training, this project has supported training activities for high-school and undergraduate students in the application of modern chemical, biophysical, and computational tools to exploring fundamental problems in RNA and chemical biology. Students published their work, giving them exposure to the scientific community and the opportunity to communicate their results to a scientifically literate yet broad audience.

Non-coding RNAs (ncRNAs), including rRNAs, microRNAs and long ncRNAs (lncRNAs), often have an architecture containing a variety of non-canonical features that are key for the molecules' structures and functions, therefore, the detailed structure provides an important backdrop to interpret functional and mechanistic studies. Small molecules that bind to specific RNA structure motifs can become powerful tools for probing RNA conformation and folding and to facilitate studies of specific RNA activities in vitro and in vivo. To date experimental structural studies of RNAs, in particular ncRNAs such as microRNAs and lncRNAs, remain to be challenging. To address this problem, a computational workflow, that integrates the NMR-defined structure information and in silico screening of virtual chemical libraries, has been developed to identify chemical compounds that selectively bind to specific non-canonical elements. Currently the program has been packaged as a zipped file and made available online (http://imdlab.org/RESSD/), including both the detailed instruction and the program itself. With this package, we have identified small molecules inhibitors against different RNA targets. The interactions of these small molecules with RNAs have been characterized using biophysical and high-resolution structure methods including NMR spectroscopy.

During the course of this project, we have made several significant discoveries in terms of biological functions of small molecules and ncRNAs in cells and in animals, and these results have been published on a variety of leading peer-reviewed high impact journals. Most recently, using our platform we identified linifanib as an inhibitor of miR-10b and this discovery was published on Sci Rep. 2018 Aug 30;8(1):13106. Another of our manuscripts modeled the transcribed ultraconserved region (UTR) 339 which was published on Nat Commun. 2017 Nov 27;8(1):1801 and got highlighted on Noncoding RNA. 2018 Sep 18;4(3), pii: E23. The manuscript describing the structure/dynamics of UU:GA motif and its interaction with 2-amino-1,3-benzothiazole-6-carboxamide will soon be submitted, and our modeling protocol is also being prepared for publication on leading peer-reviewed journals . Other related publications include a novel study of the ROR1-HER3-lncRNA signaling axis modulating the Hippo-YAP pathway to regulate bone metastasis published on Nat Cell Biol. 19 (2), 106, and an article reviewing the small molecule compounds targeting miRNAs for cancer therapy published on Adv Drug Deliv Rev. (81), 104. Additionally, based on the project two graduate students successfully defended their Ph.D. dissertations, with one titled as Targeting Oncogenic MiRNAs with Small Molecules for Breast Cancer Therapy (2015), and the other one as Computational Modeling of RNA-Small Molecule and RNA-Protein Interactions. 

Last Modified: 10/09/2018
Modified by: Shuxing Zhang