An ultrapotent pan-β-coronavirus lineage B(β-CoV-B)neutralizing antibody locks the receptor-binding domain in closed conformation by targeting its conserved epitope

New threats posed by the emerging circulating variants of SARS-CoV-2 highlight the need to find conserved neutralizing epitopes for therapeutic antibodies and efficient vaccine design.Here,we identified a receptorbinding domain(RBD)-binding antibody,XG014,which potently neutralizesβ-coronavirus lineage B(β-CoV-B),including SARS-CoV-2,its circulating variants,SARSCoV and bat SARSr-CoV WIV1.Interestingly,antibody family members competing with XG014 binding show reduced levels of cross-reactivity and induce antibodydependent SARS-CoV-2 spike(S)protein-mediated cellcell fusion,suggesting a unique mode of recognition by XG014.Structural analyses reveal that XG014 recognizes a conserved epitope outside the ACE2 binding site and completely locks RBD in the non-functional“down”conformation,while its family member XG005 directly competes with ACE2 binding and position the RBD“up”.Single administration of XG014 is effective in protection against and therapy of SARS-CoV-2 infection in vivo.Our findings suggest the potential to develop XG014 as pan-β-CoV-B therapeutics and the importance of the XG014 conserved antigenic epitope for designing broadly protective vaccines againstβ-CoV-B and newly emerging SARS-CoV-2 variants of concern.

Molecular mechanism of interaction between SARS-CoV-2 and host cells and interventional therapy

The pandemic of coronavirus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection has resulted in an unprecedented setback for global economy and health.SARS-CoV-2 has an exceptionally high level of transmissibility and extremely broad tissue tropism.However,the underlying molecular mechanism responsible for sustaining this degree of virulence remains largely unexplored.In this article,we review the current knowledge and crucial information about how SARS-CoV-2 attaches on the surface of host cells through a variety of receptors,such as ACE2,neuropilin-1,AXL,and antibody-FcyR complexes.We further explain how its spike(S)protein undergoes conformational transition from prefusion to postfusion with the help of proteases like furin,TMPRSS2,and cathepsins.We then review the ongoing experimental studies and clinical trials of antibodies,peptides,or small-molecule compounds with anti-SARS-CoV-2 activity,and discuss how these antiviral therapies targeting host-pathogen interaction could potentially suppress viral attachment,reduce the exposure of fusion peptide to curtail membrane fusion and block the formation of six-helix bundle(6-HB)fusion core.Finally,the specter of rapidly emerging SARS-CoV-2 variants deserves a serious review of broad-spectrum drugs or vaccines for long-term prevention and control of COVID-19 in the future.