SARS-CoV-2 is neutralized by proteins that block receptor-binding sites
on spikes that project from the viral envelope. In particular,
substantial research investment has advanced monoclonal antibody
therapies to the clinic where there are signs of partial efficacy in
reducing viral burden and hospitalization. An alternative is to use the
host entry receptor, ACE2, as a soluble decoy that broadly blocks
SARS-associated coronaviruses with limited potential for viral escape.
Here, we summarize efforts to engineer higher affinity variants of
soluble ACE2 that rival the potency of affinity-matured antibodies.
Strategies have also been used to increase the valency of ACE2 decoys
for avid spike interactions and to improve pharmacokinetics via IgG
fusions. Finally, the intrinsic catalytic activity of ACE2 for the
turnover of the vasoconstrictor angiotensin II may directly address
COVID-19 symptoms and protect against lung and cardiovascular injury,
conferring dual mechanisms of action unachievable by monoclonal
antibodies. Soluble ACE2 derivatives therefore have the potential to be
next generation therapeutics for addressing the immediate needs of the
current pandemic and possible future outbreaks.