Origin,virological features,immune evasion and intervention of SARS-CoV-2 Omicron sublineages

Recently,a large number of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants continuously emerged and posed a major threat to global public health.Among them,particularly,Omicron variant(B.1.1.529),first identified in November 2021,carried numerous mutations in its spike protein(S),and then quickly spread around the world.Currently,Omicron variant has expanded into more than one hundred sublineages,such as BA.1,BA.2,BA.2.12.1,BA.4 and BA.5,which have already become the globally dominant variants.Different from other variants of concern(VOCs)of SARS-CoV-2,the Omicron variant and its sublineages exhibit increased transmissibility and immune escape from neutralizing antibodies generated through previous infection or vaccination,and have caused numerous re-infections and breakthrough infections.In this prospective,we have focused on the origin,virological features,immune evasion and intervention of Omicron sublineages,which will benefit the development of nextgeneration vaccines and therapeutics,including pan-sarbecovirus and universal anti-CoV therapeutics,to combat currently circulating and future emerging Omicron sublineages as well as other SARS-CoV-2 variants.

Structural and functional basis for pan-CoV fusion inhibitors against SARS-CoV-2 and its variants with preclinical evaluation

The COVID-19 pandemic poses a global threat to public health and economy.The continuously emerging SARS-CoV-2 variants present a major challenge to the development of antiviral agents and vaccines.In this study,we identified that EK1 and cholesterol-coupled derivative of EK1,EK1C4,as pan-CoV fusion inhibitors,exhibit potent antiviral activity against SARS-CoV-2 infection in both lung-and intestine-derived cell lines(Calu-3 and Caco2,respectively).They are also effective against infection of pseudotyped SARS-CoV-2 variants B.1.1.7(Alpha)and B.l.1.248(Gamma)as well as those with mutations in S protein,including N417T,E484K,N501Y,and D614G,which are common in South African and Brazilian variants.Crystal structure revealed that EK1 targets the HR1 domain in the SARS-CoV-2 S protein to block virus-cell fusion and provide mechanistic insights into its broad and effective antiviral activity.Nasal administration of EK1 peptides to hACE2 transgenic mice significantly reduced viral titers in lung and intestinal tissues.EK1 showed good safety profiles in various animal models,supporting further clinical development of EK1-based pan-CoV fusion inhibitors against SARS-CoV-2 and its variants.