Photo: Group photo of some researchers in this study (Yin Wanchao in the front row, Fourth from right, Xu Huaqiang on the third right) Source/ Shanghai Institute of Medicine, Chinese Academy of Sciences (the same below)
The Omikejung variant has set off a "tsunami" of cases around the world. Unlike the multiple mutant strains discovered in the past two years, the number of Omilon mutation sites is large, with as many as 37 mutations in viral spike proteins. Previously, it was unclear how these mutations affected the infectivity of Ami kerong and the mechanisms that led to immune escape. Recent studies have also shown that a variety of current neutralizing antibodies against the new coronavirus are ineffective or significantly less potent than Omilon.
Xu Huaqiang and Yin Wanchao's team from the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences hastened to analyze the structure of the Aumequeron spike protein and the high-resolution cryo-EM structure that binds to the human receptor ACE2 in a short period of time, and overcame the structure of the Omicron spike protein and the specific therapeutic antibody JMB2002 with the cooperative unit. The relevant research results were recently published online in the international top academic journal "Science".
The binding receptor capacity is nearly ten times stronger
The genetic carrier of the new crown virus is RNA, the mutation frequency is high, and a variety of "worrying mutant strains" have emerged, which continues to bring new challenges to the prevention and control of the global epidemic.
Omiqueron has a dimer structure in the spike protein receptor binding domain (RBD). As far as Xu Huaqiang knows, this structure does not exist in other strains, because it is related to the mutation of Omi kerong itself.
So, what effect will the dimer structure have on the infectivity of Omikeron? "Thermodynamic experiments have shown that the RBD of the Omikejong variant is highly flexible and unstable, and its thermal dissolution temperature has been reduced by more than 5°C, making it easier for spike proteins to transition from closed to open conformations." Researcher Xu Huaqiang told reporters.
Pictured: Structure of the Aumechjong mutant strain of the new coronavirus spike protein binding receptor ACE2
On the other hand, the RBD dimer formed by the specific interaction of adjacent RBDs in the Omiqueron thorn protein trimer can make the specific RBD of the Omiljung thorn protein remain in a stable open conformation, which in turn makes it easier for the Omiljunn thorn protein to interact with the receptor ACE2, which also explains the reason for the increased infectivity of the Omiljung from the atomic level.
"Biochemical level experiments have shown that the Aumequeron variant strain of Spike Protein binding to its receptor ACE2 has a significant enhancement compared to the wild type, nearly 10 times higher." Xu Huaqiang said.
In addition, the structure analyzed by the research team also showed that most of the mutation sites of the Omiljung thorn protein have multiple antigen epitopes and are present on the surface of the protein. From a structural point of view, this explains the molecular mechanism by which Omikeron is able to resist most neutralizing antibodies.
Conquer specific therapeutic antibody structures
One hand grasps research, the other hand grasps application. With the support of the partner unit, Xu Huaqiang and Yin Wanchao's team conquered the structure of the Omicron spike protein and the specific therapeutic antibody JMB2002.
On this antibody, the collaborative team has concluded phase I clinical trials, showing strong therapeutic effect and high safety. Xu Huaqiang introduced that the results of biochemical level binding experiments show that the binding power of the antibody to the Aumequeron spike protein is 4 times higher than that of the wild-type antibody, which has great potential for inhibition of the Omiljung.
Pictured: Structure of the Omiljunn variant new coronavirus spike protein-binding antibody JMB2002
Through the analytical pathway, the researchers also obtained a complex structure and found that the JMB2002 antibody fragment binds to the back of the receptor-binding motif of RBD in a new conformation, meaning it is an antibody to a novel mechanism of action. Coupled with the results of biochemical experiments and antiviral neutralization experiments, these indicate that JMB2002 antibodies have a broad-spectrum molecular mechanism against the new crown virus. "This provides new ideas for the design and development of broad-spectrum anti-COVID-19 antibodies." Xu Huaqiang thinks.
Xu Huaqiang's team has been involved in the new crown virus research since 2020. Over the past two years, we have continued to focus on the structure and mechanism of the new crown virus. It is worth mentioning that only a few months after the outbreak of the new crown epidemic, Xu Huaqiang's team analyzed the high-resolution cryo-electron microscopy structure of the important drug target RNA replication enzyme and the inhibitor remdesivir of the new crown virus, and the results were also published in Science.
"After the emergence of Omi kerong, we found that it was different from the original coronavirus. Therefore, an emergency research team was set up to use electron microscopy and computer resources to support research in this direction. Xu Huaqiang said that from structural analysis, biochemical experiments, and paper writing, to the end of last year, the paper was launched on the preprint platform (Note: at this time, it was not peer reviewed), which took less than three weeks.
The reporter learned that this latest achievement is also the first study involving the Omicron antibody, and the binding site of the antibody is different from all the previous anti-new coronavirus antibodies.
Xu Huaqiang revealed that in basic science, the team hopes to find more potential receptors other than the ACE2 receptor in the future, and at the same time crack the cross-species transmission properties of Omi kerong from the molecular biochemical level; in terms of application, Xu Huaqiang hopes to provide inspiration for future vaccine design from a structural point of view.
Xinmin Evening News reporter Gao Yang