PT  - JOURNAL ARTICLE
AU  - Procko, Erik
TI  - The sequence of human ACE2 is suboptimal for binding the S spike protein of SARS coronavirus 2
AID  - 10.1101/2020.03.16.994236
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.03.16.994236
4099  - http://biorxiv.org/content/early/2020/03/17/2020.03.16.994236.short
4100  - http://biorxiv.org/content/early/2020/03/17/2020.03.16.994236.full
AB  - The rapid and escalating spread of SARS coronavirus 2 (SARS-CoV-2) poses an immediate public health emergency, and no approved therapeutics or vaccines are currently available. The viral spike protein S binds ACE2 on host cells to initiate molecular events that release the viral genome intracellularly. Soluble ACE2 inhibits entry of both SARS and SARS-2 coronaviruses by acting as a decoy for S binding sites, and is a candidate for therapeutic and prophylactic development. Using deep mutagenesis, variants of ACE2 are identified with increased binding to the receptor binding domain of S at a cell surface. Mutations are found across the interface and also at buried sites where they are predicted to enhance folding and presentation of the interaction epitope. The N90-glycan on ACE2 hinders association. The mutational landscape offers a blueprint for engineering high affinity ACE2 receptors to meet this unprecedented challenge.