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An ACE2 Triple Decoy that neutralizes SARS-CoV-2 shows enhanced affinity for virus variants.
Tanaka, Shiho; Nelson, Gard; Olson, C Anders; Buzko, Oleksandr; Higashide, Wendy; Shin, Annie; Gonzalez, Marcos; Taft, Justin; Patel, Roosheel; Buta, Sofija; Richardson, Ashley; Bogunovic, Dusan; Spilman, Patricia; Niazi, Kayvan; Rabizadeh, Shahrooz; Soon-Shiong, Patrick.
  • Tanaka S; ImmunityBio, Inc., 9920 Jefferson Blvd., Culver City, CA, 90232, USA. Shiho.tanaka@immunitybio.com.
  • Nelson G; ImmunityBio, Inc., 9920 Jefferson Blvd., Culver City, CA, 90232, USA.
  • Olson CA; ImmunityBio, Inc., 9920 Jefferson Blvd., Culver City, CA, 90232, USA.
  • Buzko O; ImmunityBio, Inc., 9920 Jefferson Blvd., Culver City, CA, 90232, USA.
  • Higashide W; ImmunityBio, Inc., 9920 Jefferson Blvd., Culver City, CA, 90232, USA.
  • Shin A; ImmunityBio, Inc., 9920 Jefferson Blvd., Culver City, CA, 90232, USA.
  • Gonzalez M; ImmunityBio, Inc., 9920 Jefferson Blvd., Culver City, CA, 90232, USA.
  • Taft J; Center for Inborn Errors of Immunity, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY, 10029-5674, USA.
  • Patel R; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY, 10029-5674, USA.
  • Buta S; Department of Microbiology, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY, 10029-5674, USA.
  • Richardson A; Center for Inborn Errors of Immunity, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY, 10029-5674, USA.
  • Bogunovic D; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY, 10029-5674, USA.
  • Spilman P; Center for Inborn Errors of Immunity, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY, 10029-5674, USA.
  • Niazi K; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY, 10029-5674, USA.
  • Rabizadeh S; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY, 10029-5674, USA.
  • Soon-Shiong P; Center for Inborn Errors of Immunity, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY, 10029-5674, USA.
Sci Rep ; 11(1): 12740, 2021 06 17.
Article in English | MEDLINE | ID: covidwho-1275953
ABSTRACT
The SARS-CoV-2 variants replacing the first wave strain pose an increased threat by their potential ability to escape pre-existing humoral protection. An angiotensin converting enzyme 2 (ACE2) decoy that competes with endogenous ACE2 for binding of the SARS-CoV-2 spike receptor binding domain (S RBD) and inhibits infection may offer a therapeutic option with sustained efficacy against variants. Here, we used Molecular Dynamics (MD) simulation to predict ACE2 sequence substitutions that might increase its affinity for S RBD and screened candidate ACE2 decoys in vitro. The lead ACE2(T27Y/H34A)-IgG1FC fusion protein with enhanced S RBD affinity shows greater live SARS-CoV-2 virus neutralization capability than wild type ACE2. MD simulation was used to predict the effects of S RBD variant mutations on decoy affinity that was then confirmed by testing of an ACE2 Triple Decoy that included an additional enzyme activity-deactivating H374N substitution against mutated S RBD. The ACE2 Triple Decoy maintains high affinity for mutated S RBD, displays enhanced affinity for S RBD N501Y or L452R, and has the highest affinity for S RBD with both E484K and N501Y mutations, making it a viable therapeutic option for the prevention or treatment of SARS-CoV-2 infection with a high likelihood of efficacy against variants.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Signal Transduction / Amino Acid Substitution / Drug Discovery / Molecular Dynamics Simulation / Angiotensin-Converting Enzyme 2 / SARS-CoV-2 / COVID-19 Topics: Variants Limits: Humans Language: English Journal: Sci Rep Year: 2021 Document Type: Article Affiliation country: S41598-021-91809-9

Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Signal Transduction / Amino Acid Substitution / Drug Discovery / Molecular Dynamics Simulation / Angiotensin-Converting Enzyme 2 / SARS-CoV-2 / COVID-19 Topics: Variants Limits: Humans Language: English Journal: Sci Rep Year: 2021 Document Type: Article Affiliation country: S41598-021-91809-9