Introduction
Not long following its emergence in China in late 2019, SARS coronavirus
2 (SARS-CoV-2) became an unprecedented public health emergency for our
generation. The absence of immunity, superspreader
events1 and presymptomatic2 and
asymptomatic3,4 transmission have all combined to
favor this respiratory virus’ global spread. The virus is devastating to
the elderly and other vulnerable groups with certain predisposing
conditions, and elicits surprisingly heterogenous disease symptoms
collectively known as COVID-19, with the most common being fever, dry
cough, hypoxemia and pneumonia5,6,7,8, but also
unusual neurological symptoms9 and
coagulopathy10. It remains unclear which aspects of
disease are the result of disseminated virus infection of multiple
tissues versus dysregulation of signaling pathways, including cytokine
storms11,12 and aberrant angiotensin and kinin peptide
processing13,14,15.
Virus entry is mediated by interactions between the viral spike, a
trimeric complex of protein S, and angiotensin-converting enzyme 2
(ACE2) on a host cell membrane16,17,18,19,20,21,22,23.
S is proteolytically processed as two subunits, S1 and S2, that remain
noncovalently associated until ACE2 is bound by a receptor-binding
domain (RBD) in the S1 subunit, triggering conformational changes that
include S1 shedding, exposure of a fusion peptide at the N-terminus of
S2 and fusion of the viral envelope with the host
membrane21,24,25,26,27. Antibodies targeting multiple
epitopes on S, but especially the RBD, can block ACE2 engagement or
prevent membrane fusion from occurring, and numerous monoclonal antibody
therapies are now in preclinical and clinical
development28,29,30,31,32,33. However, coronaviruses
have moderate to high mutation rates34,35 and there is
a perceived risk that drug resistant SARS-CoV-2 variants might begin
circulating once antibody therapies become widely used. This is
addressed by combining noncompeting monoclonal antibodies as
cocktails36.
An alternative strategy is to use ACE2 itself as a soluble decoy
receptor that competes for receptor-binding sites on
S22,37,38,39 (Figure 1). ACE2 is an 805 amino acid
(a.a.) protein that comprises a protease domain (a.a. 19-615), a
collectrin-like dimerization domain (a.a. 616-729) and a single-span
transmembrane domain (a.a. 741-765)16. The major
attraction of using an entry receptor as a soluble decoy is that, in
principle, the virus has limited mutational mechanisms for escape
without simultaneously losing affinity for the native, membrane anchored
form40. Soluble decoy receptors are used clinically
for a variety of indications, although none are yet approved drugs for
viruses41. Wild type, soluble ACE2 (sACE2) is an
investigational drug for acute respiratory distress that has been
rapidly repurposed as a SARS-CoV-2 antiviral37 and has
entered a phase II COVID-19 clinical trial managed by Apeiron
Biologics42. This drug candidate has become the
starting point for multiple engineering efforts to solve key issues
surrounding pharmacokinetics, affinity and avidity for the creation of
next generation ACE2 derivatives with superior efficacy. It is these
efforts that are reviewed here.