S protein is easy to mutate, can N protein take up the important task of new crown antibody drugs

Since the outbreak of the new crown epidemic, domestic and foreign research institutions have extensively carried out research on neutralizing antibodies against the new coronavirus and antibodies against cytokine storm.
Their research and development strategies mainly focus on the S protein, that is, the use of neutralization against the S protein or ACE2 protein.
The antibody binds to the S protein or ACE2 receptor on the surface of the virus particle to block the binding of the S protein to ACE2, thereby blocking the virus from entering the cell
.

However, the S protein is susceptible to mutation due to environmental pressure
.
Recently, the new coronavirus variants that have appeared around the world are caused by the mutation of the new coronavirus S protein

It is precisely because of the increased drug resistance of the virus and the increased risk of single-agent treatment failure caused by the mutation that the US Food and Drug Administration revoked the emergency use authorization of Eli Lilly's new crown antibody drug LY-CoV555 in April this year
.

Recently, "Nature Communications" published a research result jointly by the Fifth Hospital of Sun Yat-Sen University, Jinan University, Techno Microlab and other research institutions, which is expected to break the above-mentioned dilemma
.

Researchers screened and isolated the first fully human N protein antibody nCoV396 that targets the N protein of the new coronavirus based on the plasma of recovered patients with new coronaviruses who have been cured and discharged from the hospital.
They determined that the antibody recognizes the epitope of the N protein and passed the isolation.
The complement activation test of the body confirmed the important role of the allosteric regulation mechanism between nCoV396 and the N protein and its N-terminal domain in inhibiting the excessive activation of complement induced by the N protein
.

Advantages of N protein antibody

In the article, the researchers confirmed through experiments that the selected N protein antibody can activate the body's primary immune response to viral infection like the S protein antibody, and is superior to the S protein antibody in the secondary immune response effect
.

The results of sequencing studies also show that the higher mutation frequency of the N protein antibody allows it to stimulate the host to produce a stronger immune response than the S protein antibody
.

The researchers said: "nCoV396 effectively inhibits the over-activation of complement induced by N protein, and may provide better treatment effects for patients with new coronary disease who have over-activation of complement
.
"

In addition, another study published in "Nanoscale" showed that the structure of N protein has high similarity in different coronaviruses and different COVID-19 mutant strains.
Due to the conservative characteristics of N protein, it is The evolution and mutation of the new coronavirus is still in a conservative state, and the characteristic that the N protein is wrapped in the virus also allows it to be protected from the environmental pressure that causes the S protein to change
.

Subsequently, the three-dimensional computational imaging of the N protein and the binding site of the protein antibody showed that the antibody binding site of the N protein has a high degree of consistency in different strains, making the N protein have great potential to become a broad-spectrum new coronavirus antibody
.

It is understood that SARS-CoV-2 belongs to the genus of Coronavirus β, which consists of a corona envelope and a single-stranded RNA gene
.
Genomic RNA and nucleoprotein (N) are encapsulated in a phospholipid bilayer.

"S protein binds to the angiotensin-converting enzyme 2 (ACE2) membrane protein on the surface of lung epithelial cells.
ACE2 will then undergo changes in shape and structure to mediate virus entry into the cell, and use the cell’s own amino acid molecules, nuclear Acid molecules and lipid molecules synthesize new virus particles through chemical reactions.
These new virus particles are released outside the cell and infect surrounding normal cells in the same way
.
" The co-first author Wang Yueming of Jinan University told China Science Newspaper

When the host's immune system detects foreign pathogens, it activates the human natural immune system, which allows a large number of immune cells to enter the infection site and release cytokines to form a storm of factors that attack the infected cells, eventually leading to pneumonia and acute respiratory distress.
The production
.

Provide ideas for the development of new crown antibody drugs

The so-called antibody drugs refer to protein drugs containing full antibodies, antibody fragments, or genetically engineered antibodies.
Because of their specificity, high efficiency and safety in binding to target antigens, they are widely used in major diseases such as malignant tumors
.

Antibodies are immunoglobulins produced by immune cells that can specifically react with antigens after being stimulated by antigens (usually foreign proteins).
They are produced by a single B cell clone and act against a specific antigen cluster.
It is a monoclonal antibody (monoclonal antibody).
The structure of the monoclonal antibody mainly consists of two light chains (L) and two heavy chains (H), Fab fragment and Fc fragment, respectively.
The antigen binding site is on the Fab fragment, which is antibody dependent.
The cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) are mainly mediated and played by the Fc fragment
.

It is understood that according to different structures, antibody drugs can be divided into various types such as full antibodies, antibody fragments, bispecific or multispecific antibodies, antibody conjugates, and antibody fusion proteins
.
The technological development of antibody drugs has gone through four stages: murine antibody drugs, human-mouse chimeric and humanized antibody drugs, fully human antibody drugs, and natural fully human antibody drugs

During the interview, the reporter learned that the latest research results at home and abroad have revealed the relationship between mannose-binding lectin serine protease 2 (MASP-2) and N protein.
The nucleocapsid protein (N protein) of the new coronavirus is SARS.
-The protein with the highest expression level after CoV-2 infection is located in the core part of the virus particle during the assembly process of the virus, exists in the form of binding to genomic RNA, and interacts with RNA during the transcription and replication of viral RNA
.

But N protein is more conservative than other proteins such as S and M.
N protein can not only induce humoral immune response, but also induce cellular immune response
.
The researchers said that it is the combination of the N protein of the new coronavirus and MASP-2 that leads to the excessive activation of complement, which intensifies the lung damage of the patient

Industry experts believe that this result fills up the research gaps in the development of macromolecular-specific drugs targeting virus N protein and N protein-mediated abnormal complement activation, and also provides new ideas and directions for the development of global new crown antibody drugs

Related paper information: https://doi.