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.