SARS-CoV-2, the virus responsible for COVID-19, has wreaked havoc on health care systems, economies, and everyday lives worldwide. Scientists are fighting back with multiple strategies, including vaccines, repurposed drugs developed for other diseases, and brand-new therapies. Now, researchers reporting in ACS Central Science have identified small molecules that target a structure within the RNA genome of SARS-CoV-2, interfering with viral gene expression and targeting the RNA for destruction.
The SARS-CoV-2 RNA genome folds into unique shapes that can potentially be targeted by drugs. One region of the RNA, called the frameshifting element (FSE), contains a hairpin and other structures that help the virus translate its genes into proteins. Matthew Disney, Hafeez Haniff, Yuquan Tong, and colleagues wondered if they could identify a small-molecule drug that could bind to the hairpin and prevent it from doing its job. They also wanted to see if they could increase the drug’s potency by adding a component that would attract an RNA-chopping cellular enzyme to destroy the virus’ genome.
The researchers began by conducting microarray experiments to identify small molecules that bind to a specific region of the SARS-CoV-2 FSE hairpin. One molecule, which they named compound 5 (C5), decreased the hairpin’s efficiency in helping the virus translate its genes by about 25% in cell culture experiments, reducing the ability of SARS-CoV-2 to make essential proteins. To enhance the potency of C5, the team attached a molecule (called a ribonuclease-targeting chimera, or RIBOTAC) that recruits a human enzyme that degrades the viral RNA. In cultured cells, RIBOTAC increased the potency of C5 by about 10-fold.
Although much more work is needed to develop the RIBOTAC-containing compound into a drug, these findings suggest that the SARS-CoV-2 genome can be targeted by small molecules that disrupt its function, the researchers say.
For more on this discovery, read Breaking COVID-19’s “Clutch” to Stop Its Spread.
Reference: “Targeting the SARS-CoV-2 RNA Genome with Small Molecule Binders and Ribonuclease Targeting Chimera (RIBOTAC) Degraders” by Hafeez S. Haniff, Yuquan Tong, Xiaohui Liu, Jonathan L. Chen, Blessy M. Suresh, Ryan J. Andrews, Jake M. Peterson, Collin A. O’Leary, Raphael I. Benhamou, Walter N. Moss, and Matthew D. Disney, 30 September 2020, ACS Central Science.
DOI: 10.1021/acscentsci.0c00984
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