The approach could be added to existing SARS-CoV-2 antibody cocktails for greater function against emerging variants. (Photo: PTI/Representational)
Los Angeles: Researchers have engineered a novel antibody that can directly interfere with and block the cell-to-cell transmission ability of SARS-CoV-2, the virus that causes COVID-19.
The antibody, FuG1, targets the enzyme furin, which the virus uses for its efficient chain of infections in human cells.
The approach, described recently in the journal Microbiology Spectrum, could be added to existing SARS-CoV-2 antibody cocktails for greater function against emerging variants.
"We developed an approach that interferes with the transmission chain of SARS-CoV-2," said senior author of the study Jogender Tushir-Singh from the University of California (UC), Davis in the US.
"The COVID-19 vaccines are a great lifesaver in reducing hospitalisations and severe illness. Yet, we are now learning that they may not be as effective in controlling the transmissibility of the virus," Tushir-Singh said.
The researchers noted that engineered FuG1 antibody competitively interferes with the furin function needed for the SARS-CoV-2 virus to become highly transmissible.
Furin, found throughout the human body, is involved in various functions of cells. It is a type of enzyme that can break down proteins into smaller components.
Furin does this by cutting, or cleaving, the polybasic peptide bonds within the proteins, the researchers said.
It can also cleave and activate viruses that enter human cells. Pathogens that utilise furin in their human host include HIV, influenza, dengue fever and SARS-CoV-2, they said.
When SARS-CoV-2 infects a human cell, it is in its active state, having already "cleaved" its spike protein, which the SARS-CoV-2 virus uses to enter and infect the cells.
However, when the virus is being synthesised within the host cell -- when it is replicating -- the spike is in an inactive state.
The virus needs to use the host cell's furin to cut the spike protein into two parts, S1 and S2, which makes the spike active on the viral particles for efficient transmissibility upon release.
The virus exploits the host's furin to transmit from one cell to another and another. This added activation step is what makes the virus highly transmissible," said Tanmoy Mondal, the first author of the study and a post-doctoral researcher at UC Davis.
Inhibiting furin to limit the SARS-CoV-2 chain of infection cycle is not a straightforward mechanism, according to the researchers.
"Furin is found throughout the human body and is needed for the normal functioning of many biological processes. Stopping furin from doing its job causes high body toxicity. That is why the standard furin inhibitor drugs are not a clinically feasible option," Tushir-Singh said.
In the latest research, the team engineered a conjugated antibody targeting the SARS-CoV-2 spike protein.
The design is similar to therapeutic monoclonal (IgG) antibodies but includes an added feature -- Fc-extended peptide -- that specifically interferes with the host furin.
FuG1 allows the interruptions of the furin function to limit spike activation, thus specifically limiting the viral transmissibility during its chain of infection in host cells.
The high affinity, variable-domain-targeting spike in FuG1 is key for furin-targeting specificity to avoid potential toxicity.
The researchers evaluated the engineered furin disrupter, FuG1, in human lung tissue cells. Tests were run with the original SARS-CoV-2 variant and pseudoviruses.
They found that adding the furin disruptor peptide did not interfere with the function of the antibody or its ability to bind to the SARS-CoV-2 spike.
FuG1 significantly impacted the spike cleavage at furin sites. It also interfered with the overall stability of the SARS-CoV-2 spike protein, which in general is necessary for infecting cells and transmissibility of the virus.
The next steps for the team will be a series of experiments in mice. They will also test the engineered antibody against current variants like Omicron.
Tushir-Singh is cautiously optimistic that variants such as Omicron will not yield many differences.