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Characterization of Critical Determinants of ACE2-SARS CoV-2 RBD Interaction.
Int J Mol Sci. 2021 Feb 25; 22(5)IJ

Abstract

Despite sequence similarity to SARS-CoV-1, SARS-CoV-2 has demonstrated greater widespread virulence and unique challenges to researchers aiming to study its pathogenicity in humans. The interaction of the viral receptor binding domain (RBD) with its main host cell receptor, angiotensin-converting enzyme 2 (ACE2), has emerged as a critical focal point for the development of anti-viral therapeutics and vaccines. In this study, we selectively identify and characterize the impact of mutating certain amino acid residues in the RBD of SARS-CoV-2 and in ACE2, by utilizing our recently developed NanoBiT technology-based biosensor as well as pseudotyped-virus infectivity assays. Specifically, we examine the mutational effects on RBD-ACE2 binding ability, efficacy of competitive inhibitors, as well as neutralizing antibody activity. We also look at the implications the mutations may have on virus transmissibility, host susceptibility, and the virus transmission path to humans. These critical determinants of virus-host interactions may provide more effective targets for ongoing vaccines, drug development, and potentially pave the way for determining the genetic variation underlying disease severity.

Authors+Show Affiliations

Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1N 6N5, Canada.Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.Department of Biology, University of Ottawa, Ottawa, ON K1N 6N5, Canada.Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1N 6N5, Canada.Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

33668756

Citation

Brown, Emily E F., et al. "Characterization of Critical Determinants of ACE2-SARS CoV-2 RBD Interaction." International Journal of Molecular Sciences, vol. 22, no. 5, 2021.
Brown EEF, Rezaei R, Jamieson TR, et al. Characterization of Critical Determinants of ACE2-SARS CoV-2 RBD Interaction. Int J Mol Sci. 2021;22(5).
Brown, E. E. F., Rezaei, R., Jamieson, T. R., Dave, J., Martin, N. T., Singaravelu, R., Crupi, M. J. F., Boulton, S., Tucker, S., Duong, J., Poutou, J., Pelin, A., Yasavoli-Sharahi, H., Taha, Z., Arulanandam, R., Surendran, A., Ghahremani, M., Austin, B., Matar, C., ... Azad, T. (2021). Characterization of Critical Determinants of ACE2-SARS CoV-2 RBD Interaction. International Journal of Molecular Sciences, 22(5). https://doi.org/10.3390/ijms22052268
Brown EEF, et al. Characterization of Critical Determinants of ACE2-SARS CoV-2 RBD Interaction. Int J Mol Sci. 2021 Feb 25;22(5) PubMed PMID: 33668756.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Characterization of Critical Determinants of ACE2-SARS CoV-2 RBD Interaction. AU - Brown,Emily E F, AU - Rezaei,Reza, AU - Jamieson,Taylor R, AU - Dave,Jaahnavi, AU - Martin,Nikolas T, AU - Singaravelu,Ragunath, AU - Crupi,Mathieu J F, AU - Boulton,Stephen, AU - Tucker,Sarah, AU - Duong,Jessie, AU - Poutou,Joanna, AU - Pelin,Adrian, AU - Yasavoli-Sharahi,Hamed, AU - Taha,Zaid, AU - Arulanandam,Rozanne, AU - Surendran,Abera, AU - Ghahremani,Mina, AU - Austin,Bradley, AU - Matar,Chantal, AU - Diallo,Jean-Simon, AU - Bell,John C, AU - Ilkow,Carolina S, AU - Azad,Taha, Y1 - 2021/02/25/ PY - 2021/02/02/received PY - 2021/02/16/revised PY - 2021/02/21/accepted PY - 2021/3/6/entrez PY - 2021/3/7/pubmed PY - 2021/3/18/medline KW - NanoLuc Binary Technology KW - SARS-CoV-2 KW - angiotensin-converting enzyme 2 KW - bioluminescence KW - drug development KW - receptor binding domain KW - spike protein KW - vaccine development JF - International journal of molecular sciences JO - Int J Mol Sci VL - 22 IS - 5 N2 - Despite sequence similarity to SARS-CoV-1, SARS-CoV-2 has demonstrated greater widespread virulence and unique challenges to researchers aiming to study its pathogenicity in humans. The interaction of the viral receptor binding domain (RBD) with its main host cell receptor, angiotensin-converting enzyme 2 (ACE2), has emerged as a critical focal point for the development of anti-viral therapeutics and vaccines. In this study, we selectively identify and characterize the impact of mutating certain amino acid residues in the RBD of SARS-CoV-2 and in ACE2, by utilizing our recently developed NanoBiT technology-based biosensor as well as pseudotyped-virus infectivity assays. Specifically, we examine the mutational effects on RBD-ACE2 binding ability, efficacy of competitive inhibitors, as well as neutralizing antibody activity. We also look at the implications the mutations may have on virus transmissibility, host susceptibility, and the virus transmission path to humans. These critical determinants of virus-host interactions may provide more effective targets for ongoing vaccines, drug development, and potentially pave the way for determining the genetic variation underlying disease severity. SN - 1422-0067 UR - https://www.unboundmedicine.com/medline/citation/33668756/Characterization_of_Critical_Determinants_of_ACE2_SARS_CoV_2_RBD_Interaction_ DB - PRIME DP - Unbound Medicine ER -