PT  - JOURNAL ARTICLE
AU  - Youwei Xu
AU  - Canrong Wu
AU  - Xiaodan Cao
AU  - Chunyin Gu
AU  - Heng Liu
AU  - Mengting Jiang
AU  - Xiaoxi Wang
AU  - Qingning Yuan
AU  - Kai Wu
AU  - Jia Liu
AU  - Deyi Wang
AU  - Xianqing He
AU  - Xueping Wang
AU  - Su-Jun Deng
AU  - H. Eric Xu
AU  - Wanchao Yin
TI  - Structural and biochemical mechanism for increased infectivity and immune evasion of Omicron BA.1 and BA.2 variants and their mouse origins
AID  - 10.1101/2022.04.12.488075
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.04.12.488075
4099  - http://biorxiv.org/content/early/2022/04/18/2022.04.12.488075.short
4100  - http://biorxiv.org/content/early/2022/04/18/2022.04.12.488075.full
AB  - The Omicron BA.2 variant has become a dominant infective strain worldwide. Receptor binding studies reveal that the Omicron BA.2 spike trimer have 11-fold and 2-fold higher potency to human ACE2 than the spike trimer from the wildtype (WT) and Omicron BA.1 strains. The structure of the BA.2 spike trimer complexed with human ACE2 reveals that all three receptor-binding domains (RBDs) in the spike trimer are in open conformation, ready for ACE2 binding, thus providing a basis for the increased infectivity of the BA.2 strain. JMB2002, a therapeutic antibody that was shown to have efficient inhibition of Omicron BA.1, also shows potent neutralization activities against Omicron BA.2. In addition, both BA.1 and BA.2 spike trimers are able to bind to mouse ACE2 with high potency. In contrast, the WT spike trimer binds well to cat ACE2 but not to mouse ACE2. The structures of both BA.1 and BA.2 spike trimer bound to mouse ACE2 reveal the basis for their high affinity interactions. Together, these results suggest a possible evolution pathway for Omicron BA.1 and BA.2 variants from human-cat-mouse-human circle, which could have important implications in establishing an effective strategy in combating viral infection.Competing Interest StatementH.E.X., W.Y., Y.X., C.W., H.L., M.J., X.X.W., Q.Y and K.W. have declared no competing interest. S-J. D., X.C., C.G., J.L., D.W., X.H. and X.P.W., are employee of Shanghai Jemincare Pharmaceuticals, and are developing JMB2002 as a potential anti-Omicron therapeutic.