SARS-CoV-2, the virus responsible for COVID-19has devastated health systems, the economy and everyday life around the world. Scientists are fighting back with a variety of strategies, including vaccines, misused drugs designed for other diseases, and brand new therapies. Researchers are now reporting in ACS Central Science have identified small molecules that act on a structure within the RNA Genome of SARS-CoV-2 that disrupts viral gene expression and targets the RNA for destruction.
The SARS-CoV-2 RNA genome folds into unique shapes that drugs can potentially target. A region of RNA called a frameshifting element (FSE) contains a hairpin and other structures that help the virus convert its genes into proteins. Matthew Disney, Hafeez Haniff, Yuquan Tong, and colleagues wondered if they could identify a small molecule drug that could attach to the hairpin and prevent it from doing their job. They also wanted to find out if they could make the drug more effective by adding a component that attracts an RNA-hacking cellular enzyme to destroy the genome of the virus.
The researchers first performed microarray experiments to identify small molecules that bind to a specific region of the SARS-CoV-2 FSE hairpin. A molecule they named Compound 5 (C5) decreased the efficiency of the hairpin in translating its genes by the virus in cell culture experiments by about 25%, reducing the ability of SARS-CoV-2 to make essential proteins . To make C5 more effective, the team tied a molecule (called the ribonuclease targeting chimera, or RIBOTAC) that recruits a human enzyme that breaks down the viral RNA. In cultured cells, RIBOTAC increased the effectiveness of C5 by about 10-fold.
Although much more work is required to develop the compound containing RIBOTAC into a drug, these results suggest that the SARS-CoV-2 genome can be attacked by small molecules that disrupt its function, the researchers say.
For more information on this discovery, see Breaking COVID-19’s “Clutch” To Stop The Spread.
Reference: “Targeting the SARS-CoV-2 RNA Genome with Small Molecular Binding Agents and Ribonuclease Targeting Chimeras (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, September 30, 2020 ACS Central Science.
DOI: 10.1021 / acscentsci.0c00984
