A Novel Soluble ACE2 Variant with Prolonged Duration of Action Neutralizes SARS-CoV-2 Infection in Human Kidney Organoids
- 1 February 2021
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal of the American Society of Nephrology
- Vol. 32 (4), 795-803
- https://doi.org/10.1681/asn.2020101537
Abstract
Background There 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. Methods A 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. Results Whereas 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. Conclusions This 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.Keywords
Funding Information
- National Institute of Diabetes and Digestive and Kidney Diseases (RO1DK104785)
- Joseph and Bessie Feinberg Foundation
This publication has 49 references indexed in Scilit:
- Pharmacokinetics and Pharmacodynamics of Recombinant Human Angiotensin-Converting Enzyme 2 in Healthy Human SubjectsClinical Pharmacokinetics, 2013
- Angiotensin-converting enzyme 2: enhancing the degradation of angiotensin II as a potential therapy for diabetic nephropathyKidney International, 2012
- Recombinant Expression and Characterization of Human and Murine ACE2: Species-Specific Activation of the Alternative Renin-Angiotensin-SystemInternational Journal of Hypertension, 2012
- ACE2: more of Ang-(1–7) or less Ang II?Current Opinion in Nephrology and Hypertension, 2011
- Targeting the Degradation of Angiotensin II With Recombinant Angiotensin-Converting Enzyme 2Hypertension, 2010
- A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injuryNature Medicine, 2005
- Membrane-associated zinc peptidase families: comparing ACE and ACE2Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, 2004
- Angiotensin-Converting Enzyme-2 (ACE2): Comparative Modeling of the Active Site, Specificity Requirements, and Chloride DependenceBiochemistry, 2003
- Hydrolysis of Biological Peptides by Human Angiotensin-converting Enzyme-related CarboxypeptidaseJournal of Biological Chemistry, 2002
- A Human Homolog of Angiotensin-converting EnzymeJournal of Biological Chemistry, 2000