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.