Breakthrough Imaging Reveals How the Coronavirus Proofreader Thwarts Drugs
New atomic-level images at 2.4 angstroms detail the mechanism of the coronavirus proofreading enzyme, ExoN, and how it removes antiviral drugs.
Iowa State University researchers have captured the highest-resolution images ever obtained of a critical coronavirus enzyme, using cryogenic electron microscopy (cryo-EM). The images, resolving details down to 2.4 angstroms, shed light on how the virus’s proofreading machinery—exoribonuclease (ExoN)—interacts with RNA containing nucleotide analog antivirals like remdesivir, sofosbuvir, and bemnifosbuvir.
How Antivirals Are Sabotaged
The study reveals a critical vulnerability in the current treatment strategy.
The research identified how nucleotide analog antivirals alter RNA binding dynamics, making the RNA more likely to detach from the replication enzyme and attract ExoN. This process allows the virus to remove the faulty building blocks, significantly reducing drug effectiveness.
A Path to Better Treatments
Yang Yang, assistant professor at Iowa State and lead researcher, stated that the atomic snapshots provide insight into functional groups and potential modifications to make treatments more effective. The study suggests two potential strategies to outsmart the proofreader:
- Modifying nucleotide analogs so their faulty RNA products are not recognized by ExoN due to shape incompatibility.
- Increasing binding between ExoN and the RNA while reshaping ExoN to lock it in an inactive form.
Technical Achievement
The images were obtained using one of three federally funded cryo-EM centers. The marked improvement in resolution over previous work is attributed to optimized sample preparation protocols, developed partly at Iowa State's own cryo-EM facility.
Looking Ahead
The lab is now studying other nucleotide analog treatments for resistance to ExoN. Finding an existing medicine with greater resistance to proofreading could provide a faster path to improving COVID-19 treatments.