A new class of medicinal compounds that target RNA: Jennifer Hines’ laboratory at Ohio University has recently discovered a new class of compounds that target RNA and interrupt its function. This discovery led to the identification of a chemical scaffold that could be used in the future for RNA-targeted medicines. These could be used to treat viral and bacterial infections as well as cancers and metabolic diseases.
Although RNA is chemically similar to DNA, it also regulates the way that DNA’s instructions are implemented within a living cell. This essential role in cell function is what makes RNA such a desirable target.
Professor of biochemistry at the College of Arts and Sciences, Hines stated that “targeting RNA is at forefront of medicinal chemistry research with immense potential for treating diseases.” It is difficult to develop new RNA-targeted therapeutics because there are not many compounds that directly modulate RNA activity.
The Hines team determined that 4-aminoquinolines block the function of the bacterial riboswitch DNA and bind the stem-loop II motif RNA (an RNA structure in the virus responsible for the COVID-19 pandemic).
These compounds are able to bind RNA structures at very specific locations, which makes them excellent starting scaffolds for the development of therapeutics. Hines stated that this discovery was remarkable because the possibility of RNA binding was hidden in plain sight within the 4-aminoquinoline structure. However, no one had ever seen it before. “Our research revealed that 4-aminoquinolines exhibit distinct activities and chemical features that are very similar to polyamines, which are natural compounds found in cells that regulate RNA function.
“As part of a comprehensive RNA-targeted drug discovery project, our focus has been on investigating ligand/RNA binding interactions involving larger and more dynamic RNA structural motifs over the past 20 years. Hines stated that this experience was what allowed my group to respond quickly to the pandemic by investigating targeting the viral stem-loop 2 motif RNA virtually through computational studies and then in a lab.
The Hines group uses a combination of spectroscopic (fluorescence, UV-Vis, NMR); biochemical/biophysical (gel electrophoresis, isothermal titration calorimetry); and, computational (docking, molecular dynamics simulations, quantitative structure-activity calculations, bioinformatics) techniques in their RNA-targeted drug discovery studies.
Hines said, “It was in an earlier study that we first noticed 4-aminoquinolines. However, not enough information was available about the function stem-loop II motif RNA to determine what the compounds might do.”
“We then moved to investigate the functional effects of these compounds on T-box riboswitch RNA, which regulates gene transcription in bacteria. We found that the compound’s inhibitory effects were dose-dependent and very similar to that of polyamines (a class of compounds that bind RNA in cells). When I was trying to understand why this might be, I discovered the structural similarities between these two classes of compounds.
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