The structure and function of the novel coronavirus

The new bat virus is a sense RNA genome of about 30 kb, encoding 4 structural proteins, 16 non-structural proteins (nsp1-16) and some accessory proteins. Structural proteins are spike protein (S), envelope protein (E), membrane protein (M) and nucleocapsid protein (N). The S protein includes an N-terminal S1 S1 subunit responsible for receptor binding and is further divided into an N-terminal domain (NTD), a receptor domain (RBD), subregion 1 (SD1) and subregion 2 (SD2). The S2 subunit is further divided into fusion peptide (FP), heptad repeat 1 (HR1) and heptad repeat 2 (HR2).

The novel coronavirus enters the cell through S protein binding to the host cell receptor angiotensin converting enzyme 2 (ACE2). Receptor binding triggers a conformational change of the S protein. The activated S protein is cleaved by the protease TMPRSS2 at the S1/S2 site, releasing the S1 subunit, exposing the FP on the S2 subunit. FP is inserted into the target cell membrane, and HR1 and HR2 refold to form a fused conformation, which drives the fusion of the viral membrane with the target cell. Cryoelectron microscopy results of the combination of the novel coronavirus and ACE2 showed the interaction between RBD and human full-length ACE2. The novel coronavirus S protein has extensive glycosylation, which may be an important factor for the virus to bind to the cell and promote immune escape through epitope masking.

Coronaviruses encode non-structural proteins that are necessary for virus replication in cells. For example, RNA-dependent RNA polymerase is a key component of coronavirus replication and transcription mechanisms. The low-temperature electron microscope structure of the complex formed by RdRp and cofactors nsp7 and nsp8 has been obtained. The rapid development of the basic knowledge of the novel coronavirus paved the way for the discovery and development of vaccines and therapeutic drugs against COVID-19.

Vaccine development

Vaccination is the most effective way to control the infection of novel coronavirus. Studies have confirmed that S protein is the main target for stimulating the production of neutralizing antibodies and is also the focus of vaccine development. At present, there are multiple research and development approaches such as inactivated vaccines, attenuated vaccines, recombinant protein vaccines, viral vector vaccines, mRNA vaccines, DNA vaccines, etc., and some have entered the clinical stage.

Convalescent plasma therapy

The plasma of the convalescent patients (CP) can be said to be a "fire-fighting behavior". It is a kind of plasma that is produced by the convalescent patients who will produce high-titer neutralizing antibodies in the absence of specific antiviral drugs and is imported into severe patients. treatment method. During the SARS, MERS, Influenza A, and Ebola outbreaks, CP therapy showed an effect on patients to relieve clinical symptoms and reduce mortality. Currently undergoing a CP infusion trial, it is found that patients receiving CP have clinical symptoms that have disappeared or improved significantly, mortality has decreased, and no adverse events have been reported. Large-scale randomized clinical trials are also needed to prove the effectiveness and safety of CP therapy.

Neutralizing antibody therapy

Neutralizing antibodies are an important part of the host's immune response to viral pathogens. Neutralizing monoclonal antibodies have been developed to treat viral infections of RSV, influenza, Ebola, HIV, HCMV, and rabies. In SARS and MERS, adoptive input therapy of neutralizing antibodies is effective, so researchers soon started the development of novel coronavirus neutralizing antibodies. For the novel coronavirus, the main focus is on identifying neutralizing antibodies produced by natural infection and neutralizing antibodies produced by animal immunization. At present, several research teams have obtained neutralizing antibodies and entered the preclinical test stage.

Challenges of neutralizing antibody development

The first is the limitation of animal models. As written above, there is currently no animal model that can simulate COVID-19 severity. Moreover, there is still a shortage of mice with transgenic hACE2 genes worldwide, which makes it difficult to meet the needs of novel coronavirus neutralizing antibodies and drug development. The monkey model is currently the most valuable animal model. For example, the rhesus monkey and cynomolgus monkey models can simulate the clinical symptoms of human infection with the new corona virus to a certain extent. However, many teams report that due to the large differences between monkeys, more morbidity factors need to be further studied. Moreover, COVID-19 patients with underlying diseases have much higher critical and fatal rates than patients without underlying diseases. Therefore, more animal models of metabolic diseases need to be accelerated. Perhaps other types of animal models can be used in the study of new crown animals, such as ferrets, dogs, cats, etc. The second is the ADE effect. There are no reports of therapeutically neutralizing antibody-related ADE. However, the complexity of the ADE mechanism, such as antibody-virus binding mediated by Fcγ receptors, complement and complement receptor mediated, and different glycosylation modifications, may cause adverse events to patients.

Conclusion

The current COVID-19 pandemic has caused an unprecedented impact on humans, requiring all sectors of society to make an unprecedented response to fight this disease. To address the urgent need for treatment, readjusting the use of existing drugs and strategies is the logical first step. This includes testing antiviral drugs, drugs used to modulate the host's immune system, and CP transfusions as a treatment for COVID-19. The novel coronavirus is likely to remain with us as a seasonal infection. If the novel coronavirus spreads as a seasonal virus, or another coronavirus poses a serious threat in the future, developing an effective vaccine is the best weapon against COVID-19.

The mature antibody technology can isolate the neutralizing antibody of the novel coronavirus within months or even weeks. In order to better select the epitope, antibody form, and antibody combination, we must determine how fast the novel coronavirus produces escape mutations and which epitopes are more vulnerable to neutralizing antibodies. Another important consideration is the engineering of neutralizing antibody Fc to avoid potential antibody-dependent enhancement (ADE). Despite the challenges, the development of neutralizing antibodies is a key part of the COVID-19 treatment tool.

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