Tuesday, July 1, 2025 7/1/2025

Mechanism-based Targeting of the RNA Processing Machinery of SARS-CoV-2

Award Number: R01AI161363
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: 08/01/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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Mechanism-based Targeting of the RNA Processing Machinery of SARS-CoV-2 - ABSTRACT The massive global pandemic with high morbidity and mortality makes Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2) one of the deadliest viruses in recent history. It is especially noteworthy for hijacking the normal operations of human cells. To develop effective therapies, we need a better understanding of the mechanisms that permit the virus to invade cells and evade host immune restriction. SARS-CoV-2 encodes the non-structural protein (nsp)16/nsp10 protein complex that transfers a methyl group from S-adenosyl methionine (SAM) to 2’-OH of the first transcribing nucleotide of the viral mRNA and thus converts the Cap-0 (m7GpppA) to Cap-1 (m7GpppAm). The resulting viral mRNA mimics host cell’s mRNA. In this way, a cell cannot distinguish between its own RNA and that of the virus. This modification of the virally encoded mRNA not only tricks the immune system and helps the virus to take over the host translation machinery for synthesis of its own proteins for survival and propagation. Ablation of nsp16 activity should trigger an immune response to viral infection and limit pathogenesis. Our recent paper in Nature Communications described atomic level details of the nsp16/nsp10 complex and how the enzyme is well adapted to bind the RNA cap and exert the 2’-OH methylation. We also discovered a distant pocket (located 25Å away from the catalytic center) in nsp16 that is unique to SARS-CoV-2. We also found that this pocket in nsp16 is partially composed of amino acids that are unique to SARS-CoV-2. It can bind small molecules outside of the catalytic center. We propose to build a long- term research program aimed at deciphering the factors crucial to the maintenance of RNA genome and evasion from the host’s immune response. Our studies will reveal basic principles underlying SARS-CoV-2 RNA cap modification, the mode of nucleoprotein (NP) assembly, interplay with mRNA, and new approaches for therapeutic targeting. In Aim 1, we will resolve a series of new structures of nsp16/nsp10 proteins captured in every step of the methyl transfer by X-ray crystallography. The structural data will be validated by detailed biochemical and biophysical studies. We will resolve the biochemical and structural determinants of the assembly of viral RNA capping machinery, and identify factors underlying integrity of RNA genome. In Aim 2, we will develop a novel molecular tool to study temporal distribution of the RNA methylation during viral infection. We will examine new models for combinatorial inhibition of viral proteins by drug repurposing or novel small molecules. Finally, we will use our recently established reverse genetics approaches based on the use of a bacterial artificial chromosome (BAC) to generate recombinant (r)SARS-CoV2 containing mutations in nsp16 to determine their contribution in viral replication in cultured cells and pathogenesis in vivo using our recently described K18 human angiotensin converting enzyme 2 (hACE2) mouse model of SARS-CoV-2 infection and associated coronavirus disease 2019 (COVID-19).


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: 2025 ( Subtotal = -$81,554 )
2025	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	002	4	1/13/2025	EXTENSION WITH OR WITHOUT FUNDS	$11,865
2025	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	001	3	1/13/2025	SUPPLEMENT FOR EXPANSION	-$11,865
2025	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	000	3	12/16/2024	SUPPLEMENT FOR EXPANSION	$0
2025	2023	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	003	3	3/25/2025	NON-COMPETING CONTINUATION	-$81,554
														Subtotal = -$81,554

Issue Date FY: 2024 ( Subtotal = $757,310 )
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	000	3	2/22/2024	SUPPLEMENT FOR EXPANSION	$172,636
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	002	4	9/5/2024	EXTENSION WITH OR WITHOUT FUNDS	$584,674
2024	2023	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	001	3	8/15/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $757,310

Issue Date FY: 2023 ( Subtotal = $584,674 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	000	3	6/1/2023	NON-COMPETING CONTINUATION	$584,674
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	001	3	9/11/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $584,674

Issue Date FY: 2022 ( Subtotal = $626,308 )
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	000	2	7/26/2022	NON-COMPETING CONTINUATION	$626,308
														Subtotal = $626,308

Issue Date FY: 2021 ( Subtotal = $608,161 )
2021	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	000	1	7/28/2021	NEW	$608,161
														Subtotal = $608,161

Grand Total All Awards = $2,494,899

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Mechanism-based Targeting of the RNA Processing Machinery of SARS-CoV-2

Award Number: R01AI161363

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: 08/01/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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