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Designed variants of ACE2-Fc that decouple anti-SARS-CoV-2 activities from unwanted cardiovascular effects.
Liu, Pan; Xie, Xinfang; Gao, Li; Jin, Jing.
  • Liu P; Feinberg Cardiovascular and Renal Research Institute, Department of Medicine-Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • Xie X; Feinberg Cardiovascular and Renal Research Institute, Department of Medicine-Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Department of Nephrology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, China.
  • Gao L; Feinberg Cardiovascular and Renal Research Institute, Department of Medicine-Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Department of Nephrology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, China.
  • Jin J; Feinberg Cardiovascular and Renal Research Institute, Department of Medicine-Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Electronic address: jing.jin@northwestern.edu.
Int J Biol Macromol ; 165(Pt B): 1626-1633, 2020 Dec 15.
Article in English | MEDLINE | ID: covidwho-866724
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ABSTRACT
Angiotensin-converting enzyme 2 (ACE2) is the entry receptor for SARS-CoV-2, and recombinant ACE2 decoys are being evaluated as new antiviral therapies. We designed and tested an antibody-like ACE2-Fc fusion protein, which has the benefit of long pharmacological half-life and the potential to facilitate immune clearance of the virus. Out of a concern that the intrinsic catalytic activity of ACE2 may unintentionally alter the balance of its hormonal substrates and cause adverse cardiovascular effects in treatment, we performed a mutagenesis screening for inactivating the enzyme. Three mutants, R273A, H378A and E402A, completely lost their enzymatic activity for either surrogate or physiological substrates. All of them remained capable of binding SARS-CoV-2 and could suppress the transduction of a pseudotyped virus in cell culture. This study established new ACE2-Fc candidates as antiviral treatment for SARS-CoV-2 without potentially harmful side effects from ACE2's catalytic actions toward its vasoactive substrates.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Recombinant Fusion Proteins / Immunoglobulin Fc Fragments / Angiotensin-Converting Enzyme 2 / SARS-CoV-2 / COVID-19 / COVID-19 Drug Treatment Type of study: Experimental Studies Topics: Variants Limits: Animals / Female / Humans Language: English Journal: Int J Biol Macromol Year: 2020 Document Type: Article Affiliation country: J.ijbiomac.2020.10.120

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Recombinant Fusion Proteins / Immunoglobulin Fc Fragments / Angiotensin-Converting Enzyme 2 / SARS-CoV-2 / COVID-19 / COVID-19 Drug Treatment Type of study: Experimental Studies Topics: Variants Limits: Animals / Female / Humans Language: English Journal: Int J Biol Macromol Year: 2020 Document Type: Article Affiliation country: J.ijbiomac.2020.10.120