Since its discovery in November last year, the SARS-CoV-2 superstrain Omicron has rapidly spread globally and has gradually replaced the previous Variants of Concern (VOCs) that were identified in Spike There are more than 30 mutations in the protein that allow it to evade immunity from most therapeutic neutralizing antibodies and some vaccines
Therefore, the development of potent neutralizing antibodies against Omicron is of great clinical significance
On March 28, 2022, Zhu Yongqun's laboratory of the School of Biomedical Research, together with Deng Kai's laboratory of Sun Yat-sen University, Chen Zhiwei's laboratory of Hong Kong University, and Ye Lilin's laboratory of Army Medical University, published online at Cell Host & Microbe entitled "35B5 antibody potently neutralizes SARS- "CoV-2 Omicron by disrupting the N-glycan switch via a conserved Spike epitope" paper reports that 35B5, a full-spectrum human monoclonal antibody against SARS-CoV-2 VOCs, can potently neutralize Omicron and reveal its novel mechanism of action
The researchers found that the receptor-binding domain (RBD)-targeting mAb 35B5 not only potently neutralized previous VOCs, but also had nanomolar neutralization of Omicron
In order to study the structural basis of Omicron immune evasion and the potent neutralization of Omicron by 35B5, the researchers analyzed the cryo-EM structure of the Omicron Spike extracellular domain (S-ECD) complex with 35B5 Fab, and found that the Omicron S trimer has a more compact structure.
Structural packing and a more stable conformation
Further analysis of the RBD domain of Omicron showed that the 15 mutations it contained significantly changed the structure and surface electrostatic distribution of RBD, resulting in the antigenic transfer of RBD; in addition, the NTD of Omicron contained a total of 8 mutations, of which G142D and L212I were located on the surface , antigenic transfer of NTDs
So, why did these changes not affect the targeting of Omicron by 35B5? The researchers found that the epitope (epitope) of 35B5 on Omicron RBD is invariant in different VOCs, and the highly conserved epitope is the molecular basis for 35B5 targeting Omicron and other VOCs RBD
Next, the researchers analyzed why the epitope of 35B5 is so conservative? It was found that the 35B5 epitope residue is not only critical for the structural integrity of RBD and ACE2 binding, but also participates in controlling the dynamic transition of RBD conformation
The recognition of RBD by ACE2 requires the RBD to change from the down conformation to the up conformation to expose the ACE2 epitope.
The N165-glycan and N234-glycan on the NTD sandwich the two sides of the RBD like a switch that controls the conformational transition of the RBD
Among them, the N165-glycan plays a key role in maintaining the down conformation of RBD, which has a large number of interactions with the binding pocket formed by Y351, T470, F490 and L452 on the 35B5 epitope
After 35B5 binds S, the N-165 glycan is released from the binding pocket, and the N234-glycan is also completely released into the solvent, thereby opening the glycan switch, making the down RBD into an unstable up RBD, and finally leading to the S trimer dissociation, this unique glycan translocation mechanism represents a novel SARS-CoV-2 neutralization mechanism (shown above)
This work shows that 35B5's full-spectrum potent neutralization of COVID-19 VOCs and high antigen transfer tolerance make it a good candidate for clinical treatment
In this work, Wang Xiaofei, a young researcher in Zhu Yongqun's laboratory, and Tan Jiaxing and Xu Yan, a doctoral student, completed electron microscopy-related experiments and structural analysis; Chen Xiangyu, a doctoral student in Ye Lilin's laboratory, provided the 35B5 antibody and completed the pseudovirus neutralization experiment; Chen Zhiwei's experiment Dr.
Zhou Runhong, a researcher in the laboratory, completed the Omicron true virus neutralization experiment; Zhou Yan's laboratory of Zhejiang University's Institute of Microbiology and Deng Kai's laboratory of Sun Yat-sen University provided relevant experimental reagents
Original link: https://doi.