NIH VideoCast - Structural Studies of Coronavirus Fusion Glycoproteins

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Structural Studies of Coronavirus Fusion Glycoproteins

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Air date:	Wednesday, May 27, 2020, 3:00:00 PM Time displayed is Eastern Time, Washington DC Local
Views:	Total views: 1,577 (971 Live, 606 On-demand)
Category:	COVID-19
Runtime:	01:04:07
Closed captioning:	Check box to display CC outside of the video Note: You can drag the captioning window around and resize it
Description:	NIH COVID-19 SIG Lecture Series SARS-CoV-2 is a newly emerged coronavirus responsible for the current COVID-19 pandemic. Coronavirus spike (S) glycoprotein trimers promote the virus’s entry into cells and are the main targets of the humoral immune response. We demonstrated that Angiotensin-converting enzyme 2 (ACE2) is a functional entry receptor for this novel coronavirus and that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to ACE2, which correlates with the efficient spread of SARS-CoV-2 among humans. We used cryo-electron microscopy to determine the structures of the SARS-CoV-2 S ectodomain trimer, demonstrating spontaneous opening of the receptor-binding domain, and providing a blueprint for the design of vaccines and inhibitors of viral entry. SARS-CoV S murine polyclonal sera potently inhibited SARS-CoV-2 S-mediated entry into target cells, indicating that vaccination can elicit cross-neutralizing antibodies targeting conserved S epitopes. We subsequently isolated a monoclonal antibody (termed S309) from the memory B cells of an individual who recovered from SARS-CoV in 2003 and showed that S309 potently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2. Using cryo-electron microscopy and binding assays, we show that S309 recognizes a receptor-binding domain--glycan-containing epitope, which is conserved within the sarbecovirus subgenus--without competing with receptor attachment. Antibody cocktails including S309 further enhanced SARS-CoV-2 neutralization and may limit the emergence of neutralization-escape mutants. These results pave the way for using S309- and S309-containing antibody cocktails for prophylaxis in individuals at high risk of exposure or as a post-exposure therapy to limit or treat severe disease.

NLM Title:	Structural studies of coronavirus fusion glycoproteins / David Veesler, Ph.D., University of Washington.
Author:	Veesler, David. National Institutes of Health (U.S.). COVID-19 Scientific Interest Group,
Publisher:
Abstract:	(CIT): SARS-CoV-2 is a newly emerged coronavirus responsible for the current COVID-19 pandemic. Coronavirus spike (S) glycoprotein trimers promote the virus"s entry into cells and are the main targets of the humoral immune response. We demonstrated that Angiotensin-converting enzyme 2 (ACE2) is a functional entry receptor for this novel coronavirus and that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to ACE2, which correlates with the efficient spread of SARS-CoV-2 among humans. We used cryo-electron microscopy to determine the structures of the SARS-CoV-2 S ectodomain trimer, demonstrating spontaneous opening of the receptor-binding domain, and providing a blueprint for the design of vaccines and inhibitors of viral entry. SARS-CoV S murine polyclonal sera potently inhibited SARS-CoV-2 S-mediated entry into target cells, indicating that vaccination can elicit cross-neutralizing antibodies targeting conserved S epitopes. We subsequently isolated a monoclonal antibody (termed S309) from the memory B cells of an individual who recovered from SARS-CoV in 2003 and showed that S309 potently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2. Using cryo-electron microscopy and binding assays, we show that S309 recognizes a receptor-binding domain--glycan-containing epitope, which is conserved within the sarbecovirus subgenus--without competing with receptor attachment. Antibody cocktails including S309 further enhanced SARS-CoV-2 neutralization and may limit the emergence of neutralization-escape mutants. These results pave the way for using S309- and S309-containing antibody cocktails for prophylaxis in individuals at high risk of exposure or as a post-exposure therapy to limit or treat severe disease.
Subjects:	Coronaviridae Peptidyl-Dipeptidase A--physiology Spike Glycoprotein, Coronavirus--physiology
Publication Types:	Lecture Webcast

NLM Classification:	QW 168.5.C8
NLM ID:	101769623
CIT Live ID:	37501
Permanent link:	https://videocast.nih.gov/watch=37501

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