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A short report by researchers at the University of Virginia, USA, recommends the use of antibody-based treatment with a plug-and-play strategy to prevent the potential of true respiratory coronavirus syndrome 2 (SARS-CoV). -2) to attack human cells.
.jpg?resize=560%2C373&ssl=1 "Study: An innovative antibody-based Plug-and-Play strategy for SARS-CoV-2. Image credit: MattLphotography / Shutterstock")
The spike protein of SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) receptors found on human cells, allowing it to enter and take over the cell’s machinery for reproduction.
The results of the treatment show that it works by blocking the active protease-activation activity of the spike protein – one of the first steps required for viral entry.
The researchers write:
Our study reveals an analytical, safe and selective mechanistic vision for the therapeutic design of SARS-CoV-2 and is relatively relevant to future family members of coronaviridae (including mutant mutations) including exploitation of the host protease system for cell entry. ”
The study “Tactical Antibody-Based Plug-and-Play Strategy for SARS-CoV-2” is available as a preview of the bioRxiv* server, while the article is under peer review.
How they did it
The team hypothesized that they could inhibit viral fusion in host cells by targeting both the SARS-CoV-2 virus and furin near the site of viral infection. They engineered Fc 22-IgG1 – a spike protein receptor binding antibody-targeted domain. The researchers included furin substrate sites in the Fc-expanded binding region to compete with furin protease activity and inhibit viral entry. The method was named FuG1 (Furin-IgG1).
This method could be used alone for the above purpose and used to target the human lung cell antigens and the spike protein.
Findings of the study
Because 293-ACE2 cells may have folate receptor levels similar to those seen in human cancer cells, the farletuzumab team added anti-FOLR1 in FuG1 strategy. After two hours of 293-ACE2 cells were extracted and then infected with the coronary virus spike protein, farletuzumab-FuG1 antibodies, and 22-FuG1 were added.
Their results showed that FuG1 antibodies helped prevent the formation of syncytia.
As expected, FuG1 inhibited spike conversion to S2 in a dose-dependent manner. Reactivation of GAPDH in lysates indicates return of cytopathic cell state. When tested using a pseudovirus spike, 22-FuG1 also inhibited the proteolytic activation of spike to generate S2 in addition to the cells, ”the research team wrote.
The antibodies work in different ways. 22-FuG1 works by targeting furin residue after delayed spike expression. At the same time, the farletuzumab-FuG1 sheds fur by replacing FOLR1+ cells. The researchers confirmed its role and specificity with infectious cells by treating spike-cell cultures with 50µg 22-IgG1, farletuzumab-FuG1, and 22-FuG1.
Their results showed that farletuzumab-FuG1 showed a 30% reduction in risk of developing syncytia. The 22-FuG1 antibodies exhibited approximately a 90% risk reduction and a partial reduction in S2 mutation in lysates.
FuG1 antibody is selective in inhibiting SARS-CoV-2 uptake. . the two cell lines. (CD) Co-cultured cells treated with 22-IgG1, Farle- FuG1 and 22-FuG1 antibodies. (E) Number of syncytia from C (n = 3). (F) Spike-transfected whole lysates: HCC1806 cells, 293-ACE2 cells alone, and cocultured cells treated with marked antibodies were inserted for S2. (G) Recorded of the test described in H, I. (HI) Pseudoviral neutralization assays after treatment of Farle-FuG1 and 22-FuG1 antibodies at increased concentration. IC50 values are shown (n = 3).
Compared with the use of IgG1 antibodies, pseudovirus neutralization assays showed that the 22-FuG1 antibody strategy was significantly more effective in obtaining specificity against cells with spike infection. The 22-FuG1 antibodies showed a neutral ability greater than 6-fold against the spike protein.
The researchers suggest that FuG1 antibodies work to inhibit viral entry by disrupting the relationship between ACE2 expression and the receptor binding domain (RBD) of the spike protein.
The described FuG1 strategy provides a spike target centralization specificity over small furin and TMPRSS2 protectors described. In addition, a dual-based FuG1 based on heterogeneity based on lung-rich receptor targeting could be easily engineered on the basis described for high specificity. As an epitope of CR3022 is not fully involved in ACE2-RBD binding, FuG1 antibodies that severely inhibit ACE2-RBD activity are expected to be highly effective, ”the team concluded. research.
* Important message
bioRxiv publish preliminary scientific reports that are not peer-reviewed and, therefore, should not be seen as final, guiding health-related clinical practice / behavior, or be treated as information established.