RNA: New Antimicrobial Strategies

National Heart, Lung, And Blood Institute

Investigators

Linked publications & trials

Abstract

The emergence of the SARS-CoV-2 virus as the third leading cause of mortality (after cancer and cardiovascular disease) has injected great urgency in developing novel therapeutic strategies that could be employed beyond the initial round of vaccines, antibodies, and protein-targeted small molecules. The coronaviruses, of which SARS-CoV-2 is an example, employ a single-stranded RNA as both, their genome and as the template for viral protein synthesis. Analyses of coronavirus genomes in general, and the genomes of SARS-CoV-2 strain genomes have suggested the conservation of numerous highly-structured domains. Of these, the element with the best characterized function is the frameshift-promoting pseudoknot. This element allows the virus to produce two different proteins from one mRNA, by inducing the translating ribosomes to switch reading frames. It is known that abrogation of frame-shifting is lethal to the virus. To gain an detailed understanding of the frame-shifting pseudoknot, and as the first step in structure-guided anti-viral discovery, we determined the crystal structure of the SARS-CoV-2 frame-shifting pseudoknot at 1.3 resolution. This near-atomic resolution structure revealed a continuously stacked RNA domain with a number of unique, idiosyncratic pockets that are currently the target for ligand discovery. We have also investigated RNA elements of human oncogenes as potential targets for drug discovery.