Inhibition of the binding of SARS-Cov-2 to ACE2
As ACE2 is the key cellular receptor for SARS-Cov-2, approaches that
block its interaction with the virus have the potential to maintain ACE2
activity and its generation of products, such as ANG (1-7) that
counteract pathological actions of ANG II. One such approach is to use
soluble ACE2 as a decoy to bind the virus and spare cellular ACE2 (Zhang
et al., 2020). A recombinant human ACE2, GSK2586881, has been tested and
was well-tolerated in Phase 1 studies and a Phase 2 trial with ARDS
patients (Khan et al., 2017). GSK2586881 was shown to reduce circulating
levels of ANG II and Interleukin-6 (IL-6). However, this study was not
powered to verify effects on clinical endpoints and direct therapeutic
effects on the lungs were unclear. A clinical trial investigating use of
recombinant human ACE2 in COVID-19 was initiated in China, but
enrollment was subsequently withdrawn (Clinical Trials.gov identifier
NCT04287686). Linkage of the extracellular domain of the ACE2 protein to
human immunoglobulin G Fc domain is a strategy that could have
advantages for treatment of COVID-19, including prolongation of the
half-life of ACE2 (Kruse, 2020; Liu P et al, 2018). A related “decoy
approach” is the use of the receptor binding domain (RBD) of the SARS S
protein that interacts with ACE2 (Wong et al., 2004; Han et al., 2006);
this approach has not yet been tested in patients. Small molecules have
been identified as inhibitors of coronavirus binding to ACE2 (Adedeji et
al., 2013) but their efficacy has only been evaluated in limited
pre-clinical studies (Adedeji & Sarafianos, 2014). All these
approaches, which block viral entry into cells, maintain ACE2 activity
and thus would be expected to blunt disease pathobiology. By contrast,
agents that block later steps in viral infectivity (e.g., cellular
entry, endosomal inhibition, etc.) will likely yield decrease in ACE2
activity, which may be counterproductive with respect to the generation
of beneficial ACE2-derived peptides.