Researchers Use a Novel Approach to Design a COVID-19 Antiviral Drug

Solving atomic structure and binding for improved antiviral drugs.

Image courtesy of Oak Ridge National Laboratory
Neutrons and X-rays provided insights on the binding of the COVID-19 virus SARS-CoV-2 protein with a novel inhibitor, BBH-1, formed by combining atomic features of known hepatitis C and SARS-CoV-1 inhibitors (such as Boceprevir and GC-376, upper left).

The Science

Antiviral drugs are critical to treating COVID-19, but they need to be tailored at the atomic level to work effectively. In this study, researchers combined the features of clinical drugs to treat hepatitis C and viruses similar to COVID-19, such as SARS-CoV-1. This allowed them to synthesize BBH-1, a promising inhibitor that targets the breakdown of the SARS-CoV-2 virus that causes COVID-19. Inhibitors are drugs that prevent viruses from entering the body, replicating, or otherwise spreading. The researchers characterized samples using X-ray and neutron diffraction techniques to provide atomic-level insights on the structure of the BBH-1 inhibitor and how it binds to the SARS-CoV-2 protein to stop the virus from replicating. The results open routes to designing new drugs for treating COVID-19.

The Impact

Researchers created an inhibitor (BBH-1) and characterized how the inhibitor interacts with the SARS-Cov-2 protein. This BBH-1 inhibitor is a hybrid—it combines features from previous antiviral treatments for other diseases. The goal was to develop promising drug candidates for treating COVID-19. Neutron and X-ray techniques provided unique atomic structural insights. Together, these techniques allow researchers to map hydrogen atoms and ionizable functional groups. This helps them evaluate how well a candidate inhibitor binds and inhibits SARS-CoV-2 protein. The researchers visualized key part of the binding process and demonstrated it in cell-based assays. The use-inspired approach sheds light on how antiviral drugs interact with the SARS-CoV-2 virus. It also helps show how these drugs can be improved to advance COVID-19 therapeutics for all variants.


COVID-19 continues to disrupt everyday life, and emerging strains (variants) of the SARS-CoV-2 virus that causes COVID-19 threaten the effectiveness of current vaccines. Antiviral drugs that can be used as therapeutic treatment for patients diagnosed with coronavirus disease remain critical, though few are available. As part of an efficient pathway for designing and developing drugs to combat COVID-19, this study created an inhibitor that targets a specific part of the virus and blocks it from replicating. Such new insights on the fundamental mechanisms at work are important to advancing tailor-made inhibitors at molecular levels.

To enable drug discovery, researchers synthesized a novel inhibitor using a hybrid approach that combines features of several previous antivirals such as for treating hepatitis C. They characterized the results using several DOE Office of Science user facilities, including the Center for Nanophase Materials Sciences, the Spallation Neutron Source, and the High Flux Isotope Reactor, as well as the Institut Laue-Langevin, France.  Joint neutron and X-ray techniques made it possible to obtain new atomic-level details of the inhibitor’s interactions with SARS-CoV-2. These results provide critical insights for future drug design for other diseases as well.


Andrey Kovalevsky
Neutron Scattering Division
Oak Ridge National Laboratory

Peter V. Bonnesen
Center for Nanophase Materials Sciences
Oak Ridge National Laboratory


This research used resources at the Center for Nanophase Materials Sciences, the Spallation Neutron Source, and the High Flux Isotope Reactor, all of which are Department of Energy (DOE) Office of Science user facilities under the DOE Office of Science, Basic Energy Sciences program. The research also used resources at the Institut Laue-Langevin, France, and Oak Ridge National Laboratory’s Center for Structural Molecular Biology funded by the DOE Office of Science, Biological and Environmental Research program. Additional support was provided by the National Institutes of Health.


Kneller, D.W., et al., Covalent narlaprevir- and boceprevir-derived hybrid inhibitors of SARS-CoV-2 main protease. Nature Communications 13, 2268 (2022). [DOI: 10.1038/s41467-022-29915-z]

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Program: BER , BES , SUF

Performer: University , DOE Laboratory , SC User Facilities , BES User Facilities , HFIR , SNS , CNMS

Additional: Collaborations , Non-DOE Interagency Collaboration , International Collaboration