Cryo electron microscopy structure of the inhibitor longHR2_45 (shown in red) bound to the HR1 portion of the SARS-CoV-2 spike protein (shown in light blue). Credit: Image courtesy of Kailu Yang
By creating a drug based on part of the
Other treatments for COVID-19 have worked by sticking the outside of the spike protein to prevent it from infecting cells, but they’ve had downsides. For example, bebtelovimab was an antibody treatment that targeted the spike protein, however, it did not work well against novel variants of COVID-19 because that part of the spike protein mutated over time. Yang and Brunger hope their molecule, which they call the longHR2_42 inhibitor, is the lead compound for developing a new type of antiviral therapeutic to prevent infections even with new variants.
The reason the longHR2_42 inhibitor can work against an evolving virus is that it’s based on a part of the spike protein that hasn’t changed, even though other parts have. “In the virus, there are two parts of the spike protein that come together to form this bundle. So we just took a little piece of part of that packet, and by chemically synthesizing that little piece, it can fit into the spike protein and prevent the virus from infecting cells,” Brunger explained. Research prior to this COVID-19 pandemic aimed to create a similar molecule that would work to block SARS coronavirus infection, but those past attempts were not as effective as the longHR2_42 inhibitor.
Brunger thinks their molecule is more efficient than past attempts due to Yang’s work determining a detailed structure of the twisted-together parts of the SARS-CoV-2 virus, called the so-called HR1HR2 post-fusion complex, so they knew that longer molecules would help block the spike protein from twisting into the HR1HR2 complex in the first place. “We made the molecule a bit longer than previously published work based on the structure, and indeed we confirmed in our fusion and infection tests that this longer piece inhibits much better,” said Browner.
The team is currently testing the longHR2_42 inhibitor in mice infected with SARS-CoV-2 (collaboration with Giuseppe Ballisteri and colleagues, University of Finland). They hope to be able to deliver it to people via an inhaler so that it reaches the airways, which is exactly where you want to treat an infection early to prevent the infection from getting worse. “The moment people start to develop sniffles will be the time to take it,” Brunger explained.
Reference: “Nanomolar inhibition of SARS-CoV-2 infection by an unmodified peptide targeting the spike protein hairpin intermediate” by Kailu Yang, Chuchu Wang, Alex JB Kreutzberger, Ravi Ojha, Suvi Kuivanen, Sergio Couoh-Cardel, Serena Muratcioglu, Timothy J. Eisen, K. Ian White, Richard G. Held, Subu Subramanian, Kendra Marcus, Richard A. Pfuetzner, Luis Esquivies, Catherine A. Doyle, John Kuriyan, Olli Vapalahti, Giuseppe Balistreri, Tom Kirchhausen and Axel T. Brunger, September 19, 2022, Proceedings of the National Academy of Sciences.
DOI: 10.1073/pnas.2210990119