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iNature
Emerging SARS-CoV-2 variants often have many mutations in the spike(S) protein S1 subunit and are undermining the efficacy
of current vaccines and antibody therapies.
This requires the development of anti-variant SARS-CoV-2 vaccines
for the more conserved regions of the S protein.
On November 10, 2022, Zheng Yongtang, Kunming Institute of Zoology, Chinese Academy of Sciences, Ouyang Songying of Fujian Normal University and Jiang Shibo of Fudan University jointly communicated at Cell Research (IF= 46) Published online titled "A variant-proof SARS-CoV-2 vaccine targeting.
"
HR1 domain in S2 subunit of spike protein", which develops an anti-variant SARS-CoV-2 targeting the HR1 domain of the spike protein S2 subunit Vaccines
.
The recombinant subunit vaccine HR121 was designed to target the conserved HR1 domain in the S2 subunit of S protein
。 HR121 consists of HR1-linker1-HR2-linker2-HR1, conformationally and functionally fusing HR1 in the intermediate conformation with the S2 subunit The domains are similar
.
Immunizing HR121 in rabbits and rhesus macaques produces potent cross-neutralizing antibodies against SARS-CoV-2 and its variants, particularly the Omicron subtype
.
The HR121 vaccine received near-complete protection against SARS-CoV-2 infection in hACE2 transgenic mice, Syrian golden hamsters and rhesus macaques, and Omicron BA.
2 in Syrian golden hamsters The infection is effectively protected
.
The study shows that HR121 is a promising vaccine candidate for an anti-variant SARS-CoV-2 vaccine that has a new conserved target in the S2 subunit that can be used against current and future vaccines SARS-CoV-2 variants
.
In addition, on November 5, 2022, Zhang Lei, Shen Xihui of Northwest A&F University and Ouyang Songying of Fujian Normal University jointly published a newsletter entitled " Autoinducer-2 and bile salts induce c-di-GMP synthesis to repress the T3SS via a T3SS chaperone", the results of which support a model in which , Bacteria sense changes in population density and host-derived cues to regulate c-di-GMP synthesis, thereby modulating T3SS activity through c-di-GMP-responsive T3SS chaperones (click to read)
。
On November 2, 2022, Ouyang Songying's team from Fujian Normal University published an online report entitled "Structural insights into target DNA recognition and cleavage by the CRISPR-Cas12c1 system" online at Nucleic Acids Research (IF=19).
", which conducted structural studies
of target DNA recognition and cleavage through the CRISPR-Cas12c1 system.
The study's findings provide valuable information for developing the CRISPR-Cas12c1 system into an efficient, high-fidelity genome editing tool (click to read).
vaccines and therapeutics.
The spike protein(S) mediates the entry of SARS-CoV-2 by binding its S1 subunit to the host receptor angiotensin converting enzyme 2 (ACE2), Subsequently, viral and cell membrane fusion is facilitated through its S2 subunit, resulting in the release of the viral genome into the
cytoplasm.
The S1 subunit, particularly its receptor-binding domain (RBD) and N-terminal domain (NTD), induces dominant neutralizing antibodies in the host ( nAb) and serves as the primary antigen
in vaccine design.
However, selective pressure from the host acts on the S1 subunit in one way, increasing the number of mutations for the same number of
new variants.
This "domino" effect is steadily weakening the effectiveness of some current antibodies and vaccines, and is leading to constant and possible breakthrough infections in vaccinated individuals from certain variants such as Delta Omicron BA.
1 and its sublines, including BA.
2, BA.
3, BA.
4 and BA.
5, and other emerging recombinant or hybrid variants
.
Design and characterization of recombinant protein HR121 (Figure from Cell Research) The S2 subunit is different from the S1 subunit.
It is buried within the S protein in a pre-fusion conformation, inducing a small amount of nAbs against SARSCoV-2 after viral infection or vaccination with its whole amino acid sequence.
The S2 subunit contains two important domains, heptameric repeat 1 (HR1) and heptameric repeat 2 (HR2), which are highly conserved
in coronaviruses.
According to the currently recognized membrane fusion model for class I enveloped viruses (such as HIV-1, influenza virus, and coronavirus), when S2 Fusion occurs when hydrophobic fusion peptides (FPs) in homotrimers are inserted into the host cell membrane.
Thus, HR1 and HR2 adjacent to the FP are instantly exposed, forming a "fusion intermediate" or "Hairpin intermediate" conformation
.
Subsequently, the three HR2 polypeptides are moved backward in reverse parallel and folded into the three surface grooves of the HR1 trimer α-helical core, forming an irreversible one 6-α-helix bundle (6-HB) structure that maintains close contact between the virus and the cell membrane and promotes membrane fusion
.
In this process, some HR2-derived peptides bind to HR1 trimers and rare monoclonal antibodies (mAbs) to HR2 It has a high affinity and can interfere with the conformational transition of HR domains from 6-HB fusion intermediate to post-fusion structures, thus showing resistance to multiple SARSCoV-2 variants, coronaviruses, and even HIV-1 broad-spectrum antiviral activity
.
Therefore, the conserved HR1 and HR2 domains present in the intermediate conformation of S2 subunit fusion may be potential targets for vaccine development
.
However, previous reports of HIV-1- and influenza viruses have suggested that fusion intermediates are transient and unstable, and its structure in enveloped viruses has so far not been addressed, making it difficult to design an immunogen capable of mimicking its conformation and excitation of highly active nAbs in vivo
。 For example, a major study of HIV-1 used the core regions of HR1 and HR2 to design a 5-helical protein that would truncate three HR1 and two truncated HR2 are concatenated together (including HR1 - HR2 - HR1 - HR2 - HR1).
This protein lacks an HR2 helix; Thus, one of the surface grooves in the HR1 trimer kernel is not occupied and can serve as an epitope for HR1
.
However, monoclonal antibodies targeting this vacancy exhibit weak anti-HIV-1 activity only in the sub-nanomolar range
.
The study also found that the 5 helix protein of human respiratory syncytial virus (hRSV) has a pair of hRSV<b2 <b22>7> Only faint nAb titers
are produced.
In addition, several other studies on HIV-1 have developed some HR1-based trimers consisting of three different truncated HR1s, such as N35CCG-N13 , (CCIZN36)3, (CCIPN36)3, and N46FdFc, but nAbs induced by these proteins Proved to be equally weak and unsatisfactory
.
In this study, the study provides a new strategy to develop a SARS-CoV-2 vaccine
.
The study designed a recombinant protein HR121 from SARS-CoV-2 that highly mimics the conformation of the HR1 trimer kernel in S2 subunit fusion intermediates
。 HR121 immunity induced against SARS-CoV-2 and its major variants (including the current pandemic Omicron subspectrum BA.
1, BA.
2 , BA.
3, BA.
4/5).
In addition, vaccination with this protein provided almost complete protection against SARS-CoV2 prototype (hereinafter referred to as SARS-CoV-2) infection in Syrian hamsters and rhesus macaques, and against Syrian hamsters The Omicron BA.
2 variant challenge provides effective protection
.
Therefore, this study shows that the conserved HR1 domain in the S2 subunit mimics the fusion intermediate conformation, which can be used as a new target for the development of vaccines against variants of
SARS-CoV-2 or pansabecovirus.
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The content is [iNature]
