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Mechanism and Inhibition of SARS-CoV-2 Entry

Award Number: R01AI163019
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/08/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Mechanism and Inhibition of SARS-CoV-2 Entry - The long term goal of this study is to understand how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of coronavirus disease 2019 (COVID-19), enters cells and how to block that process through the use of therapeutics. Like other enveloped viruses, SARS-CoV-2 cell entry begins with engagement at the cell-surface and is completed on release of the viral contents following membrane fusion. During the process of cell entry, the SARS-CoV-2 spike protein (S) engages the cellular receptor, angiotensin converting enzyme (ACE2). Proteolytic activation of S is required to activate the fusion machinery which can be achieved by cell surface or endosomal proteases positing a model of cell surface and endosomal entry routes that depend on engagement of different host-cell molecules that vary among cell types. To interrogate the entry pathway of SARS-CoV-2 we developed a set of unique tools that permit application of single virion imaging approaches to track productive entry routes in an unbiased way and to help identify host factors coopted during viral entry. This imaging is facilitated by the use of a chimeric vesicular stomatitis virus (VSV) in which its glycoprotein gene (G) was replaced with the spike (S) gene of SARS-CoV-2. Inhibition of VSV-SARS-CoV-2 infection with monoclonal antibodies, soluble receptor and small molecule inhibitors correlates closely with inhibition of a clinical isolate of SARS-CoV-2, corroborating that the chimera is an effective BSL2 surrogate to study SARS-CoV-2 S-mediated entry. This permits us to genetically modify a core protein of the VSV ribonucleoprotein core to render the particles visible by fluorescent microscopy. By combining this imaging approach, with genetic, chemical and biological perturbations, we will map the entry routes of VSV-SARS-CoV-2 and then examine the effect of those perturbations on infection of cells with a clinical isolate of SARS-CoV-2. We will use this approach to determine how countermeasures currently in clinical trials including monoclonal antibodies, soluble ACE2, and two small molecule inhibitors apilimod and nafamostat block entry. Using genome-wide loss-of-function screens we will also interrogate the requirements for entry of SARS-CoV-2, under native and perturbed conditions to uncover new host proteins that are coopted during entry as potential additional targets for therapeutic intervention. Successful completion of this work will define the entry pathways that lead to productive SARS-CoV-2 infection, inform the mechanism by which multiple molecules in clinical development interfere with that process and unearth new host factors that are coopted during the entry pathway.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $752,346 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Allergy and Infectious Diseases Research	000	4	6/11/2024	NON-COMPETING CONTINUATION	$752,346
														Subtotal = $752,346

Issue Date FY: 2023 ( Subtotal = $752,346 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	3	6/23/2023	NON-COMPETING CONTINUATION	$752,346
														Subtotal = $752,346

Issue Date FY: 2022 ( Subtotal = $752,346 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	2	7/1/2022	NON-COMPETING CONTINUATION	$752,346
														Subtotal = $752,346

Issue Date FY: 2021 ( Subtotal = $766,721 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	1	7/8/2021	NEW	$766,721
														Subtotal = $766,721

Grand Total All Awards = $3,023,759

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Mechanism and Inhibition of SARS-CoV-2 Entry

Award Number: R01AI163019

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/08/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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