Thursday, April 25, 2024 4/25/2024

Targeting early metastable intermediates of the SARS-CoV-2 spike for vaccine and therapeutics development

Award Number: R01AI145687
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

View Award Abstract

Targeting early metastable intermediates of the SARS-CoV-2 spike for vaccine and therapeutics development The ongoing global pandemic of the novel SARS-CoV-2 presents an urgent need for development of effective preventative and treatment therapies. The viral-host cell fusion (S) protein spike is a prime target for such therapies owing to its critical role in the virus lifecycle. The S protein is divided into two regions: the N-terminal S1 domain that caps the C-terminal S2 fusion domain. Binding to host receptor via the Receptor Binding Domain (RBD) in S1 is followed by proteolytic cleavage of the spike by host proteases. This leads dramatic conformational transitions resulting in S1 shedding and exposure of the fusion machinery in S2, culminating in host-cell entry. Class I fusion proteins such as the CoV S protein that undergo large conformational changes during the fusion process must, by necessity, be highly flexible and dynamic. Indeed, cryo-EM structures of the SARS-CoV-2 spike reveal considerable flexibility and dynamics in the S1 domain, especially around the RBD that exhibits two discrete conformational states – a “down” state that is shielded from receptor binding, and an “up” state that is receptor-accessible. The overall goals of this study are to use our robust, high-throughput computational and experimental pipeline to define the detailed trajectory of the “down” to “up” transition of the SARS-CoV-2 S protein, identify early metastable intermediates in the fusion pathway, and exploit their structures and dynamics for identifying drug and vaccine candidates that target SARS-CoV-2. A wealth of structural information on CoV spike proteins, including recently determined cryo-EM structures of the SARS-CoV-2 spike, provides a rich source of detailed data from which to begin precise examination of macromolecular transitions underlying triggering of this fusion machine. The scientific premise of this study is that understanding the structural dynamics and early transition kinetics of mobile regions of the SARS-CoV-2 spike will allow optimal control of vaccine and drug responses, and facilitate the development of novel antiviral drugs and protective vaccines. At the culmination of this study, we expect to have determined structures of multiple “down”, “up”, and intermediate states of the SARS-CoV-2 S protein. Together, these studies will provide important atomically detailed structural and mechanistic information for exploitation in vaccine and therapeutics design.


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: 2023 ( Subtotal = $761,299 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	000	5	1/12/2023	NON-COMPETING CONTINUATION	$770,818
2023	2021	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	001	3	6/23/2023	SUPPLEMENT FOR EXPANSION	-$9,519
														Subtotal = $761,299

Issue Date FY: 2022 ( Subtotal = $779,673 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	4	1/19/2022	NON-COMPETING CONTINUATION	$779,673
														Subtotal = $779,673

Issue Date FY: 2021 ( Subtotal = $1,510,467 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	001	3	1/26/2021	SUPPLEMENT FOR EXPANSION	$771,293
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	3	1/22/2021	NON-COMPETING CONTINUATION	$739,174
														Subtotal = $1,510,467

Issue Date FY: 2020 ( Subtotal = $1,466,173 )
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	001	2	5/21/2020	SUPPLEMENT FOR EXPANSION	$732,990
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	2	1/28/2020	NON-COMPETING CONTINUATION	$733,183
														Subtotal = $1,466,173

Issue Date FY: 2019 ( Subtotal = $758,709 )
2019	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	1	1/25/2019	NEW	$758,709
														Subtotal = $758,709

Grand Total All Awards = $5,276,321

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Targeting early metastable intermediates of the SARS-CoV-2 spike for vaccine and therapeutics development

Award Number: R01AI145687

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer