Soluble forms of ACE2 have recently been shown to inhibit SARS-CoV-2 infection. We
report on an improved soluble ACE2, termed a "
microbody" in which the ACE2 ectodomain is fused to Fc domain 3 of the
immunoglobulin heavy chain. The
protein is smaller than previously described ACE2-Ig Fc fusion
proteins and contains an H345A
mutation in the ACE2 catalytic
active site that inactivates the
enzyme without reducing its affinity for the
SARS-CoV-2 spike. The
disulfide-bonded ACE2
microbody protein inhibited entry of lentiviral
SARS-CoV-2 spike
protein pseudotyped
virus and live
SARS-CoV-2 with a
potency 10-fold higher than unmodified soluble ACE2 and was active after initial
virus binding to the
cell. The ACE2
microbody inhibited the entry of ACE2-specific {beta}
coronaviruses and
viruses with the high infectivity variant D614G spike. The ACE2
microbody may be a valuable
therapeutic for COVID-19 that is active against
SARS-CoV-2 variants and
future coronaviruses that may arise.