Team Identifies Small Molecules That Target SARS-CoV-2 RNA for Destruction

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.

Reference: Haniff HS, Tong Y, Liu X, et al. Targeting the SARS-CoV-2 RNA Genome with Small Molecule Binders and Ribonuclease Targeting Chimera (RIBOTAC) Degraders. ACS Cent Sci. 2020. doi:10.1021/acscentsci.0c00984

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