UC Davis researchers targeted furin to block activation of spike protein, the key to the coronavirus’ infectiousness
By BRANDON NGUYEN — science@theaggie.org
Vaccines have tremendously reduced positive cases of COVID-19 since their implementation, but researchers at UC Davis Health have been looking into areas where the vaccines could be improved. Though they provide immunity, one area that is still of concern is that vaccines do not directly reduce the virus’ transmissibility, even among those who are vaccinated.
Dr. Jogender Tushir-Singh, an associate professor in the UC Davis Department of Medical Microbiology and Immunology and senior author of the study, designed and engineered, with the help of his lab, a novel antibody called FuG1, which can reduce the transmissibility of SARS-CoV-2.
“One thing that differentiates SARS-CoV-2 in 2019 versus SARS-CoV-1, which came in 2003 to 2004, is that, while they’re very similar in their genomes and spike protein sequence, SARS-CoV-2 has acquired these furin sites,” Singh said. “So I thought if these sites are unique to SARS-CoV-2, why don’t we just target these sites which will be a good criteria to reduce its pathogenicity?”
Furin is a protease, a protein that acts like molecular scissors to cleave proteins into smaller components. Oftentimes, furin cleavage is used to activate proteins, and SARS-CoV-2 is one of many viruses that takes advantage of the host’s furin to activate its spike proteins by cleaving it.
Dr. Tanmoy Mondal, the first author of the study and a postdoctoral researcher in Singh’s lab, underscored furin’s role in making the coronavirus highly transmissible.
“The virus exploits the host’s furin to easily transmit from cell to cell,” Mondal said. “When the virus makes the spike protein, the whole protein cannot infect anyone. But after cleavage by furin, the spike protein now has its infectious function, and this added activation step is what makes the virus highly transmissible.”
However, the inhibition of furin is not straightforward, as furin is still needed in daily cellular activities. Thus, specificity in the engineered antibody is crucial to its efficacy.
“Furin is found throughout the human body and is needed for the normal functioning of many biological processes,” Singh said. “Stopping furin from doing its job causes high body toxicity. That is why the standard furin inhibitor drugs are not a clinically feasible option.”
Singh and Mondal achieved this specificity in their engineered antibody by having “two faces” on the antibody: one that can target the spike protein and one that disrupts furin interaction with the spike protein.
“As host cell-enriched furin-mediated cleavage of SARS-CoV-2 spike protein is critical for viral entry and chain of the infection cycle, the solution described here [in this study] of an antibody Fc-conjugated furin competing peptide is significant,” the study, published in Microbiology Spectrum, reads. “The proposed furin competing strategy confers a broad-spectrum targeting design to impede the production of efficiently transmissible SARS-CoV-2 viral particles. In addition, the proposed approach is plug-and-play against other potentially deadly viruses that exploit secretory pathway independent host protease machinery to gain cellular entry and subsequent transmissions to host cells.”
With FuG1 as a potential antibody to be added to current antibody cocktail treatments, Singh expressed optimism toward the reduction of transmissibility in not only SARS-CoV-2 but also other viruses and pathogens that rely on furin cleavage. Currently, Singh’s lab is working on testing the antibody in mouse models with the hope that the antibody will eventually reach the clinical stages to be implemented into medical treatments for human patients.
“Our approach is a two-pronged approach, and so even if an antibody loses its effectiveness in binding due to a virus gaining mutations over time, the furin component can still work,” Singh said. “We hope that, compared to these current short-term antibodies that target spike protein and ACE2 receptor interaction, what we have engineered can be a little bit better and be more cost-effective. As long as newly emerging SARS-CoV-2 variants do not interfere with FuG1 antibody binding, it is highly likely this sort of strategy would interfere with viral transmissibility and can be applied to other pathogens that rely on furin cleavage.”
Written by: Brandon Nguyen — science@theaggie.org
