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An ACE2 Triple Decoy that neutralizes SARS-CoV-2 shows enhanced affinity for virus variants.
Sci Rep. 2021 Jun 17; 11(1):12740.SR

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.

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Authors+Show Affiliations

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. Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY, 10029-5674, USA. Department of Microbiology, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY, 10029-5674, USA.
Patel R
Center for Inborn Errors of Immunity, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY, 10029-5674, USA. Department of Pediatrics, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY, 10029-5674, USA.
Buta S
Center for Inborn Errors of Immunity, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY, 10029-5674, USA. Department of Pediatrics, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY, 10029-5674, USA. Precision Immunology Institute, 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. Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY, 10029-5674, USA. Department of Microbiology, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY, 10029-5674, USA. Department of Pediatrics, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY, 10029-5674, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY, 10029-5674, USA.
Bogunovic D
Center for Inborn Errors of Immunity, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY, 10029-5674, USA. Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY, 10029-5674, USA. Department of Microbiology, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY, 10029-5674, USA. Department of Pediatrics, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY, 10029-5674, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY, 10029-5674, USA.
Spilman P
ImmunityBio, Inc., 9920 Jefferson Blvd., Culver City, CA, 90232, USA.
Niazi K
ImmunityBio, Inc., 9920 Jefferson Blvd., Culver City, CA, 90232, USA.
Rabizadeh S
ImmunityBio, Inc., 9920 Jefferson Blvd., Culver City, CA, 90232, USA.
Soon-Shiong P
ImmunityBio, Inc., 9920 Jefferson Blvd., Culver City, CA, 90232, USA.

MeSH

Amino Acid SequenceAmino Acid SubstitutionAngiotensin-Converting Enzyme 2Antiviral AgentsCOVID-19Drug DiscoveryHumansMolecular Dynamics SimulationMutationProtein BindingProtein DomainsSARS-CoV-2Signal TransductionSpike Glycoprotein, CoronavirusVirus Internalization

Pub Type(s)

Journal Article

Language

eng

PubMed ID

34140558

Citation

Tanaka, Shiho, et al. "An ACE2 Triple Decoy That Neutralizes SARS-CoV-2 Shows Enhanced Affinity for Virus Variants." Scientific Reports, vol. 11, no. 1, 2021, p. 12740.
Tanaka S, Nelson G, Olson CA, et al. An ACE2 Triple Decoy that neutralizes SARS-CoV-2 shows enhanced affinity for virus variants. Sci Rep. 2021;11(1):12740.
Tanaka, S., Nelson, G., Olson, C. A., Buzko, O., Higashide, W., Shin, A., Gonzalez, M., Taft, J., Patel, R., Buta, S., Richardson, A., Bogunovic, D., Spilman, P., Niazi, K., Rabizadeh, S., & Soon-Shiong, P. (2021). An ACE2 Triple Decoy that neutralizes SARS-CoV-2 shows enhanced affinity for virus variants. Scientific Reports, 11(1), 12740. https://doi.org/10.1038/s41598-021-91809-9
Tanaka S, et al. An ACE2 Triple Decoy That Neutralizes SARS-CoV-2 Shows Enhanced Affinity for Virus Variants. Sci Rep. 2021 Jun 17;11(1):12740. PubMed PMID: 34140558.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - An ACE2 Triple Decoy that neutralizes SARS-CoV-2 shows enhanced affinity for virus variants. AU - Tanaka,Shiho, AU - Nelson,Gard, AU - Olson,C Anders, AU - Buzko,Oleksandr, AU - Higashide,Wendy, AU - Shin,Annie, AU - Gonzalez,Marcos, AU - Taft,Justin, AU - Patel,Roosheel, AU - Buta,Sofija, AU - Richardson,Ashley, AU - Bogunovic,Dusan, AU - Spilman,Patricia, AU - Niazi,Kayvan, AU - Rabizadeh,Shahrooz, AU - Soon-Shiong,Patrick, Y1 - 2021/06/17/ PY - 2021/3/25/received PY - 2021/5/26/accepted PY - 2021/6/18/entrez PY - 2021/6/19/pubmed PY - 2021/7/8/medline SP - 12740 EP - 12740 JF - Scientific reports JO - Sci Rep VL - 11 IS - 1 N2 - 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. SN - 2045-2322 UR - https://www.unboundmedicine.com/medline/citation/34140558/An_ACE2_Triple_Decoy_that_neutralizes_SARS_CoV_2_shows_enhanced_affinity_for_virus_variants_ DB - PRIME DP - Unbound Medicine ER -