Mutations from bat ACE2 orthologs markedly enhance ACE2-Fc neutralization of SARS-CoV-2.

BioRxiv : the Preprint Server for Biology
Huihui MouMichael Farzan

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein mediates infection of cells expressing angiotensin-converting enzyme 2 (ACE2). ACE2 is also the viral receptor of SARS-CoV (SARS-CoV-1), a related coronavirus that emerged in 2002-2003. Horseshoe bats (genus Rhinolophus ) are presumed to be the original reservoir of both viruses, and a SARS-like coronavirus, RaTG13, closely related SARS-CoV-2, has been isolated from one horseshoe-bat species. Here we characterize the ability of S-protein receptor-binding domains (RBDs) of SARS-CoV-1, SARS-CoV-2, and RaTG13 to bind a range of ACE2 orthologs. We observed that the SARS-CoV-2 RBD bound human, pangolin, and horseshoe bat ( R. macrotis) ACE2 more efficiently than the SARS-CoV-1 or RaTG13 RBD. Only the RaTG13 RBD bound rodent ACE2 orthologs efficiently. Five mutations drawn from ACE2 orthologs of nine Rhinolophus species enhanced human ACE2 binding to the SARS-CoV-2 RBD and neutralization of SARS-CoV-2 by an immunoadhesin form of human ACE2 (ACE2-Fc). Two of these mutations impaired neutralization of SARS-CoV-1. An ACE2-Fc variant bearing all five mutations neutralized SARS-CoV-2 five-fold more efficiently than human ACE2-Fc. These data narrow the poten...Continue Reading

Citations

Dec 19, 2020·Proceedings of the National Academy of Sciences of the United States of America·Kefang LiuGeorge Fu Gao
Oct 24, 2020·Proceedings of the National Academy of Sciences of the United States of America·Anum GlasgowJames A Wells
Jan 19, 2021·Current Genetic Medicine Reports·Phoebe EllisGary R McLean

Methods Mentioned

BETA
flow cytometry
surface plasmon resonance
chip
glycosylation
transfection
flow
Antibody Capture

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