A novel soluble ACE2 protein protects from lethal SARS-CoV-2 infection

ABSTRACT

Background: Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) uses full-length angiotensin converting enzyme 2 (ACE2) as the main receptor to enter the target cells. A novel soluble ACE2 protein with increased duration of action and binding capacity to exert a decoy effect as a way to intercept SARS-CoV-2 from binding to membrane-bound ACE2 was generated. The protein was administered to a lethal mouse model of COVID-19 to examine its efficacy. Methods: A human soluble ACE2 variant fused with a 5kD albumin binding domain (ABD) was linked via a dimerization motif hinge-like 4-cysteine dodecapeptide to improve binding capacity to the SARS-CoV-2. This novel protein (ACE2 1-618-DDCABD) was administered intranasally and intraperitoneally prior to viral inoculation and on the two following consecutive days. Infected animals were observed for weight, clinical score and mortality in a BSL-3 facility. Upon sacrifice, lung histopathology was evaluated, and viral loads were measured by plaque assay. Results: Infected mice that received ACE2-1-618-DDC-ABD developed only moderate disease assessed by a clinical score, modest weight loss and lung histology. At 6 days, mortality was totally prevented in the treated group (figure), lung histopathology was markedly improved and viral lung and brain titers reduced or non-detectable. By contrast, in untreated animals, lung histology revealed extensive pulmonary alveolar hemorrhage and mononuclear infiltrates, and they all became severely ill and had to be euthanized by day 6/7 (figure). Conclusions: This study demonstrates for the first time in vivo the preventative/ therapeutic efficacy of a soluble ACE2 protein in a preclinical animal model.