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trial investigating use of recombinant human ACE2 in COVID-19 was initiated in China, but enrollment was subsequently withdrawn (Clinical Trials.gov identifier NCT04287686).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.