A Novel Soluble ACE2 Variant with Prolonged Duration of Action Neutralizes SARS-CoV-2 Infection in Human Kidney Organoids

Abstract

BackgroundThere is an urgent need for approaches to prevent and treat SARS-CoV-2 infection. Administration of soluble ACE2 protein acting as a decoy to bind to SARS-CoV-2 should limit viral uptake mediated by binding to membrane-bound full-length ACE2, and further therapeutic benefit should result from ensuring enzymatic ACE2 activity to affected organs in patients with COVID-19.MethodsA short variant of human soluble ACE2 protein consisting of 618 amino acids (hACE2 1–618) was generated and fused with an albumin binding domain (ABD) using an artificial gene encoding ABDCon, with improved albumin binding affinity. Human kidney organoids were used for infectivity studies of SARS-CoV-2 in a BSL-3 facility to examine the neutralizing effect of these novel ACE2 variants.ResultsWhereas plasma ACE2 activity of the naked ACE2 1–618 and ACE2 1–740 lasted about 8 hours, the ACE2 1–618-ABD resulted in substantial activity at 96 hours, and it was still biologically active 3 days after injection. Human kidney organoids express ACE2 and TMPRSS2, and when infected with SARS-CoV-2, our modified long-acting ACE2 variant neutralized infection.ConclusionsThis novel ACE2 1–618-ABD can neutralize SARS-CoV-2 infectivity in human kidney organoids, and its prolonged duration of action should ensure improved efficacy to prevent viral escape and dosing convenience.

Plasma ACE2 predicts outcome of COVID-19 in hospitalized patients

“…Therefore, the direct blockade of ACE2, by removing the physiological brakes on the angiotensin system, could have detrimental effects on COVID-19 disease. For these reasons, an alternative strategy to inhibit the interaction of SARS-CoV-2 with ACE2 could be the administration of recombinant soluble ACE2 as a decoy receptor, which has been previously tested in small clinical trials in acute respiratory distress syndrome [ 39 ] and is now being explored in COVID-19 disease [ 40 – 42 ]. However, the level of circulating ACE2 does not necessarily reflect the expression of ACE2 in the plasma membrane of host cells.…”

Emerging SARS-CoV-2 variants of concern and potential intervention approaches

“…Different engineered variants of human recombinant soluble ACE2 (hrACE2), were reported to significantly inhibit SARS-CoV-2 infection in vitro and causing sustained viral entry blockade upon engagement of hrACE2 with the RBD in SARS-CoV-2 S protein with high affinity [79][80][81]. This is a potentially powerful treatment against SARS-CoV-2 VOCs as it can exploit the increase S-protein host receptor-binding affinity caused by S-mutations, toward increasing S-protein affinity to hrACE2.…”

The SARS-CoV-2/Receptor Axis in Heart and Blood Vessels: A Crisp Update on COVID-19 Disease with Cardiovascular Complications

“…Nevertheless, it has been demonstrated that the human recombinant sACE2 tends to decrease angiotensin II and concomitantly increases Ang 1–7 [ 58 , 59 , 60 ]. Furthermore, the generated soluble variant of ACE2 serves as a decoy receptor and binds to the spike proteins of SARS-CoV-2 virion in order to limit the virus uptake by membrane-bound ACE2 receptors [ 61 ]. These issues further interrogate whether the circulating native sACE2 could exert a protection against angiotensin II mediated cardiac dysfunction or could it effectively bind to SARS-CoV-2 spike protein as the patients with comorbid conditions, including heart failure or CAD are more vulnerable to the SARS-CoV-2 mediated severity, despite elevated sACE2 levels in their circulation.…”