Science Shanghai Institute of Materia Medica Xu Huaqiang/Yin Wanchao Reveal the Molecular Mechanism of Rapid Spread and Immune Escape of Omicron Variants

The iNature COVID-19 pandemic continues worldwide with many variants, especially the variant of concern (VOC)
.

 One recent VOC, Omicron (B.
1.
1.
529), has acquired a large number of mutations in the receptor-binding domain (RBD) of the spike protein, drawing intense scientific and public attention
.

On February 8, 2022, Science published a collaboration between the team of Xu Huaqiang/Yin Wanchao from Shanghai Institute of Materia Medica, Chinese Academy of Sciences, and the team of Jimin Xinxin Deng Sujun, entitled "Structures of the Omicron Spike trimer with ACE2 and an anti-Omicron antibody.
"The latest achievement, the study analyzed the spike protein of the poisonous Omicron mutant strain, and the high-resolution cryo-electron microscope structure that binds to its receptor ACE2 and the broad-spectrum anti-COVID-19 antibody JMB2002, respectively.
The molecular mechanism of rapid spread and immune escape of mutant strains, and revealed a new mechanism of action of the therapeutic antibody JMB2002, providing new ideas for the design and development of broad-spectrum anti-COVID-19 antibodies
.

Since the outbreak of the new crown epidemic, the number of confirmed cases worldwide has exceeded 388 million, and the death toll has exceeded 5.
7 million
.

Because the genetic carrier of the new coronavirus is RNA and the mutation frequency is high, it has evolved a variety of "worrisome mutant strains", which continue to bring uncertainty and new challenges to the global epidemic prevention and control, especially the latest Omicron mutation.
strains are raging around the world, causing a new round of infection peaks
.

Different from a variety of mutant strains discovered in the past two years, the new coronavirus Omicron mutant has the largest number of mutation sites, especially in the virus spike protein with as many as 37 mutations
.

Currently, it is unclear how these mutations affect the infectivity of Omicron variants and the mechanisms leading to immune escape
.

Recent studies have shown that more than 80% of neutralizing antibodies against 2019-nCoV are ineffective against Omicron variant strains, or their efficacy is significantly reduced.
Therefore, we have a deep understanding of the molecular mechanism of Omicron variant strain transmission and infection, and develop specific Omicron variant strains.
Antibodies for sex therapy are imminent
.

Figure 1 The structure of the Omicron mutant SARS-CoV-2 spike protein-binding receptor ACE2
.

A shows the overall conformation of the Omicron mutant spike protein bound to ACE2, B shows the RBD-RBD dimer, and the interaction interface between RBD and ACE2, and C shows the thermal stability analysis of the spike protein
.

The team of Xu Huaqiang/Yin Wanchao from Shanghai Institute of Materia Medica, Chinese Academy of Sciences has been following the needs of anti-epidemic research since the outbreak of the new crown virus.
The preliminary work aimed at the new coronavirus gene replicase RdRp, and for the first time expounded the inhibitory mechanism of the nucleoside inhibitor remdesivir (Science 368(6498):1499-1504.
); resolved the high-resolution structure of its first non-nucleoside inhibitor suramin and explained the inhibition mechanism (Nat Struct Mol Biol 28(3): 319-325.
); participated in Developed an oral nucleoside inhibitor VV116 (Cell Res 31(11): 1212-1214.
), which has obtained emergency use authorization in some countries and regions
.

This time the Omicron mutant strains spread, Xu Huaqiang/Yin Wanchao team acted quickly and urgently tackled key problems.
It took less than 3 weeks from project initiation to paper submission to analyze the spike protein of Omicron mutant strains and high-resolution freezing that binds to the human receptor ACE2.
SEM structure (Figure 1A and 1B)
.

[Video 1] The biochemical level experiment of the complex structure of Omicron Spike protein and the viral receptor ACE2 shows that the Omicron mutant spike protein binds its receptor ACE2 significantly more than the wild type, nearly 10 times higher; from the analyzed structure, it can be seen that It was observed that the adjacent RBD-specific interactions within the spike protein trimer of the Omicron variant strains, resulting in the formation of RBD dimers (Fig.
1B), can stabilize the spike protein-specific RBD of the Omicron variant strain in an open state; thermodynamics Experiments showed that the RBD of the Omicron variant is highly flexible and unstable, and its thermal dissolution temperature is reduced by more than 5 °C (Fig.
1C), which makes the spike protein more easily switch from the closed to the open conformation
.

The interaction and instability of Omicron mutant spike protein RBD promotes the interaction between Omicron mutant spike protein and ACE2, which explains the potential mechanism of Omicron mutant infectivity enhancement at the atomic level
.

At the same time, the structure analyzed by the research team showed that most of the mutation sites of the spike protein of the Omicron variant strain are located on the surface of the protein, including multiple antigenic epitopes, which structurally explains that the Omicron variant strain can resist most of the molecules of neutralizing antibodies mechanism
.

Figure 2 Structure of the Omicron variant 2019-nCoV spike protein-binding antibody JMB2002
.

A shows the overall structure of the JMB2002 antibody bound to the Omicron variant spike protein, B shows the conformation of the Omicron variant spike protein in the structure that binds the JMB2002 antibody, C shows the structure comparison of the two RBDs bound to the JMB2002 antibody, and D shows the JMB2002 antibody Combined with the RBD-RBD dimer in the structure of the spike protein of the Omicron variant strain, E shows that the bound JMB2002 antibody hinders the recognition of the receptor ACE2, F is the classification of anti-new coronavirus neutralizing antibodies, and JMB2002 antibody is a new type of antibody, which is into the fifth category
.

In cooperation with Jimin Xinxin Deng Sujun's team, Xu Huaqiang and Yin Wanchao's team from Shanghai Institute of Materia Medica, Chinese Academy of Sciences further conquered the structure of Omicron mutant spike protein and specific therapeutic antibody JMB2002 (Figure 2A-C)
.

The antibody has completed a phase one clinical trial and has strong therapeutic effect and high safety
.

Biochemical level binding experiments showed that the antibody had 4 times the binding force to the spike protein of the Omicron variant strain than to the wild type, showing a strong potential to inhibit the Omicron variant strain
.

[Video 2] Complex structure of Omicron Spike protein and antiviral receptor antibody From the analyzed complex structure, the research team found that the adjacent RBDs in the spike protein trimer of Omicron mutants also have specific interactions and form stable RBDs dimer (Fig.
2D), which shows that RBD dimer is a unique structural feature of Omicron mutant spike protein and plays an important role in its function; structural comparison shows that the bound JMB2002 antibody blocks the receptor ACE2 Recognition (Fig.
2E), meanwhile, the JMB2002 antibody fragment binds to the back of the RBD receptor-binding motif in a novel conformation, an antibody with a novel mechanism of action (Fig.
2F)
.

Combining biochemical and antiviral neutralization experiments, the research team expounded the molecular mechanism that the antibody JMB2002 has broad-spectrum anti-COVID-19
.

Researcher Yin Wanchao, Dr.
Xu Youwei and Dr.
Xu Peiyu, and postdoctoral fellow Wu Canrong, and Dr.
Cao Xiaodan and Dr.
Gu Chunyin from Jimin Trust are the co-first authors of this paper
.

Researcher Xu Huaqiang, researcher Yin Wanchao and Jimin Xinxin Dr.
Deng Sujun of Shanghai Institute of Materia Medica are the co-corresponding authors of this article
.

This work has been funded by major projects of science and technology at the municipal level of Shanghai, the National Natural Science Foundation of China, the major science and technology projects of the National Health Commission, and the pilot project of the Chinese Academy of Sciences
.

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