New Class of Medicinal Compounds that Target RNA

A team of undergraduate and also graduate chemistry students in Jennifer Hines’ laboratory at Ohio University recently uncovered a current class of compounds that can target RNA and disrupt its function. This discovery determined a chemical scaffold that might ultimately be utilized in the development of RNA-targeted medicines to treat bacterial and viral infections, along with cancer as well as metabolic illness.

RNA vs DNA

RNA is chemically like DNA; however, it likewise manages the extent to which the DNA’s instructions are executed within a living cell. This crucial regulatory role in the cell’s function turns RNA into an attractive target.

“Trying to target RNA is at the forefront of medicinal chemistry study with huge potential for treating diseases,” stated Hines, professor of chemistry and biochemistry in the University of Arts and Sciences. “However, there are relatively few compounds understood to directly modulate RNA activity, that makes it challenging to design new RNA-targeted therapeutics.”

The Hines team established that 4-aminoquinolines prevent the feature of the microbial T-box riboswitch RNA and also bind the stem-loop II theme RNA (an RNA structure located in the infection leading to the COVID-19 pandemic).

“The compounds bind these RNA structures in extremely specific sites, making them great starting scaffolds for designing specific therapeutics. What was so surprising concern this discovery is that the probability for RNA binding was hiding in plain sight within the 4-aminoquinoline framework; however, no one had determined it before,” Hines said.

“Our study determined that 4-aminoquinolines have different activities and chemical features extremely comparable to polyamines which are natural substances in the cell that modulate RNA function.”

RNA Target Drug Discovery

Hines stated that his team has been focused on examining ligand-RNA binding interactions, including larger and more dynamic RNA structural motifs, as part of a comprehensive RNA-targeted drug discovery project for over two decades. This extensive experience allowed his team to promptly respond to the pandemic by investigating the targeting of the viral stem-loop II motif RNA through computational research studies and laboratory experiments.

The Hines team uses a mix of spectroscopic (fluorescence, UV-Vis, NMR); biochemical/biophysical (gel electrophoresis, isothermal titration calorimetry); also computational (docking, molecular dynamics simulations, quantitative structure-activity calculations, bioinformatics), methods in their RNA-targeted drug discovery studies.

“It was in this earlier research where we initially noticed the 4-aminoquinolines, but not enough was understood about the function of the stem-loop II motif RNA to discern what the compounds could be doing,” Hines added.

“As a result, we shifted to exploring the functional effect of these substances on the T-box riboswitch RNA, which manages gene expression in bacteria. In these riboswitch studies, we discovered that the compound’s inhibitory effect was dose-dependent in a way very comparable to the dose-dependency of polyamines, a class of compounds that typically bind RNA in the cell. It was in puzzling out why this may be the instance when I noticed the structural resemblance between the two classes of compounds.”

Read the original article on PHYS.

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