Friday, April 19, 2024 4/19/2024

MECHANISM OF RNA SYNTHESIS AND 5'-CAPPING BY DENGUE VIRUS NS5 POLYMERASE

Award Number: R01AI087856
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

Flaviviruses including dengue, West Nile, and Zika viruses, pose significant threats as emerging diseases and potential bioterror agents. Despite the considerable impact of flavivirus infection on world-wide health, no antiviral therapies are available, and existing flavivirus vaccines are of limited utility. Our long-term goal is to obtain detailed structural and biochemical information regarding the flavivirus replication complex and to use this information for the development of antiviral therapeutics and vaccines. The flavivirus replication complex, consisting of virally-encoded non-structural proteins (NS), unidentified cellular proteins, and the viral RNA genome, is responsible for copying the viral genome and 5' RNA capping. However, how the various components of the replication machinery are arranged as a functional complex is not known. Specifically, the 5' RNA capping machinery is functionally and physically linked to the replication machinery as multi-domain (i.e., methyltransferase (MTase) and RNA-dependent RNA polymerase (RdRp) within NS5) and larger multi- protein (i.e., NS3 and NS5) complexes, but little is known regarding how RNA synthesis and RNA capping are coordinated. We have recently determined the crystal structure of the full-length dengue virus (DENV) NS5, in which MTase and RdRp could coordinate their respective activities in both monomer and dimer configurations. In the current application, we will determine how NS5 interacts with viral RNA and the NS3 protein, two other essential components in the viral replication complex. In Aim 1, we will probe how NS5 interacts with the 5' end of viral RNA, called stem loop A (SLA), to promote viral RNA synthesis. We will determine the structure of the SLA by cryo-electron microscopy, and its interactions with NS5 by a competition binding assay. In Aim 2, we will determine specific interactions among NS3 and NS5 domains during coordination of RNA synthesis and 5' RNA capping using infectious DENV RNA. In Aim 3, we will determine the X-ray crystal structures of NS5 and its RNA complexes, including SLA, dsRNA, and a `dual' substrate that binds simultaneously to both MTase and RdRp domains to represent different steps along the viral replication pathway. The combined structural, biochemical, and virological studies will help elucidate the mechanism for coordinated RNA synthesis and capping reactions in NS5.


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 = $0 )
2024	2022	TRUSTEES OF INDIANA UNIVERSITY	107 S INDIANA AVE	BLOOMINGTON	IN	47405	MONROE	USA	Allergy and Infectious Diseases Research	002	11	1/11/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2024	2022	TRUSTEES OF INDIANA UNIVERSITY	107 S INDIANA AVE	BLOOMINGTON	IN	47405	MONROE	USA	Allergy and Infectious Diseases Research	001	11	10/26/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$88,321
2024	2022	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	10	10/26/2023	NON-COMPETING CONTINUATION	-$88,321
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	10	11/28/2022	NON-COMPETING CONTINUATION	-$218,973
2023	2022	TRUSTEES OF INDIANA UNIVERSITY	107 S INDIANA AVE	BLOOMINGTON	IN	47405	MONROE	USA	Allergy and Infectious Diseases Research	001	11	11/28/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$218,973
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $378,772 )
2022	2022	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	001	10	1/11/2022	NON-COMPETING CONTINUATION	$378,830
2022	2016	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	5	10/1/2021	SUPPLEMENT FOR EXPANSION	-$58
														Subtotal = $378,772

Issue Date FY: 2021 ( Subtotal = $378,830 )
2021	2021	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	9	1/11/2021	NON-COMPETING CONTINUATION	$378,830
														Subtotal = $378,830

Issue Date FY: 2020 ( Subtotal = $378,830 )
2020	2020	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	8	1/17/2020	NON-COMPETING CONTINUATION	$378,830
														Subtotal = $378,830

Issue Date FY: 2019 ( Subtotal = $378,830 )
2019	2019	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	7	1/31/2019	NON-COMPETING CONTINUATION	$378,830
2019	2018	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	004	6	4/25/2019	COMPETING CONTINUATION	$29,855
2019	2016	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	003	5	4/25/2019	SUPPLEMENT FOR EXPANSION	-$29,855
2019	2016	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	002	5	4/25/2019	SUPPLEMENT FOR EXPANSION	$111
2019	2015	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	001	5	4/25/2019	NON-COMPETING CONTINUATION	-$111
														Subtotal = $378,830

Issue Date FY: 2018 ( Subtotal = $402,215 )
2018	2018	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	002	6	2/9/2018	COMPETING CONTINUATION	$402,215
2018	2018	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	003	6	4/27/2018	COMPETING CONTINUATION	$0
2018	2016	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	005	5	7/11/2018	SUPPLEMENT FOR EXPANSION	$29,719
2018	2016	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	001	5	2/5/2018	SUPPLEMENT FOR EXPANSION	$0
2018	2015	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	004	5	7/11/2018	NON-COMPETING CONTINUATION	-$29,719
2018	2015	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	5	2/5/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $402,215

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2015	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	5	2/3/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $295,022 )
2016	2016	UNIVERSITY OF TEXAS, MEDICAL BRANCH AT GALVESTON	1000 STRAND	GALVESTON	TX	77550	GALVESTON	USA	Allergy and Infectious Diseases Research	000	5	4/20/2016	SUPPLEMENT FOR EXPANSION	$295,022
														Subtotal = $295,022

Issue Date FY: 2015 ( Subtotal = $382,750 )
2015	2015	UNIVERSITY OF TEXAS, MEDICAL BRANCH AT GALVESTON	1000 STRAND	GALVESTON	TX	77550	GALVESTON	USA	Allergy and Infectious Diseases Research	000	5	2/17/2015	NON-COMPETING CONTINUATION	$382,750
														Subtotal = $382,750

Issue Date FY: 2014 ( Subtotal = $382,750 )
2014	2014	UNIVERSITY OF TEXAS, MEDICAL BRANCH AT GALVESTON	1000 STRAND	GALVESTON	TX	77550	GALVESTON	USA	Allergy and Infectious Diseases Research	000	4	2/20/2014	NON-COMPETING CONTINUATION	$382,750
														Subtotal = $382,750

Issue Date FY: 2013 ( Subtotal = $359,785 )
2013	2013	UNIVERSITY OF TEXAS, MEDICAL BRANCH AT GALVESTON	1000 STRAND	GALVESTON	TX	77550	GALVESTON	USA	Allergy and Infectious Diseases Research	001	3	8/8/2013	NON-COMPETING CONTINUATION	$15,310
2013	2013	UNIVERSITY OF TEXAS, MEDICAL BRANCH AT GALVESTON	1000 STRAND	GALVESTON	TX	77550	GALVESTON	USA	Allergy and Infectious Diseases Research	000	3	2/12/2013	NON-COMPETING CONTINUATION	$344,475
														Subtotal = $359,785

Issue Date FY: 2012 ( Subtotal = $382,750 )
2012	2012	UNIVERSITY OF TEXAS, MEDICAL BRANCH AT GALVESTON	1000 STRAND	GALVESTON	TX	77550	GALVESTON	USA	Allergy and Infectious Diseases Research	000	2	2/15/2012	NON-COMPETING CONTINUATION	$382,750
														Subtotal = $382,750

Issue Date FY: 2011 ( Subtotal = $381,806 )
2011	2011	UNIVERSITY OF TEXAS, MEDICAL BRANCH AT GALVESTON	1000 STRAND	GALVESTON	TX	77550	GALVESTON	USA	Allergy and Infectious Diseases Research	000	1	3/9/2011	NEW	$381,806
														Subtotal = $381,806

Grand Total All Awards = $4,102,340

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MECHANISM OF RNA SYNTHESIS AND 5'-CAPPING BY DENGUE VIRUS NS5 POLYMERASE

Award Number: R01AI087856

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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