RNA: New Antimicrobial Strategies

National Heart, Lung, And Blood Institute

Investigators

Linked publications, trials & patents

Abstract

In this review period, we characterized a bacterial gene-regulatory RNA and discovered that it functions under a kinetic-control regime, and also determined the cryogenic-sample electron microscopy (cryoEM, cryo-EM) structures of key regulatory RNA elements from the Rous Sarcoma Virus (the first oncogenic virus discovered over 40-years ago) and the SARS-CoV-2 coronavirus. Many clinically important viruses expand the coding potential of their genome employing a strategy called programmed ribosomal frameshifting. Because the success of this strategy, which relies on specific RNA elements of the viral genome is essential for viral replication, it represents an important potential target for the discovery of new antivirals, and in the case of oncogenic viruses, cancer. The Rous Sarcoma Virus frameshifting stimulatory element was the first such element, and was discovered in 1982; yet, its structure had remained elusive. Through a methodologically novel combination of biochemsitry, cryoEM and X-ray crystallography, we determined the high-resolution structure of this RNA. Our atomistic analysis reveals that the RNA can adopt several similar but distinctly different conformations. This, and structure-guided biochemistry, suggests that the conformational entropy (energetic degeneracy) of the Rous Sarcoma Virus element is critical in its regulatory role. Our structure provides the starting point of small molecule compounds that can hyoper-stabilize the RNA element and thus lead to its dysfunction. Such compounds would constitute leads into the development of completely new classes of antiviral and anti-cancer drugs.