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Structure, function, and inhibition of the SARS-CoV-2 replication-transcription complex

Award Number: R01AI161278
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: 08/06/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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Structure, function, and inhibition of the SARS-CoV-2 replication-transcription complex - Project Summary/Abstract Structure, function, and inhibition of the SARS-CoV-2 replication-transcription complex. The COVID-19 pandemic underscored the need for effective antivirals against coronaviruses (CoVs). SARS-CoV-2 replicates and transcribes its RNA genome using an RNA-dependent RNA polymerase (RdRp, subunits nsp7/nsp82/nsp12), the target of FDA-approved remdesivir (Rdv) and molnupiravir. In addition to its essential RdRp activity, nsp12 has a nidovirus-specific NiRAN domain essential for viral RNA capping. The RdRp coordinates with other key partners, including the nsp13 helicase and the nsp10/nsp14 proofreading assembly, themselves potential antiviral targets. We reported the first SARS-CoV-2 RdRp-nsp13 structures, revealing how helicase activity can drive RdRp backtracking, likely important for proofreading and/or template switching during sub-genomic RNA synthesis. We also determined the structural basis for selective Rdv-triphosphate incorporation over its natural counterpart ATP, and provided key mechanistic insights into NiRAN function. These advances position us to address fundamental unaswered questions about viral RNA synthesis and its inhibition. Aim 1. Determine the structural basis of template-dependent inhibition and resistance of the RdRp to remdesivir. After incorporation of Rdv-monophosphate (RMP) in viral RNA, that RNA becomes a compromised template. We will determine cryo-electron microscopy (cryo-EM) structures of RdRp on RMP- containing templates and of a clinical resistance variant to rigorously delineate the template-dependent inhibition and resistance mechanisms. Aim 2. Structurally and functionally characterize viral protein complexes containing [Fe4-S4]2+ clusters. Increasing evidence indicates that key SARS-CoV-2 enzymes contain oxygen-sensitive [Fe4-S4]2+ clusters. We will purify and characterize these enzymes under anaerobic conditions, providing a new structural framework for understanding CoV RNA processing enzymes and opening new avenues for antiviral development. Aim 3. Elucidate the structural determinants of NiRAN-mediated RNAylation and accelerate NiRAN inhibitor discovery through in silico docking. The NiRAN domain remains an underexploited target. Using PPCP-RNA, we will determine structure of an nsp9 RNAylation intermediate, and we will conduct ultra-large scale structure-based docking and biochemical validation to identify and optimize NiRAN inhibitors Impact: SARS-CoV-2 RNA synthesis remains a central target for antiviral therapy. These studies will provide a mechanistic blueprint for RdRp inhibition and resistance, uncover previously unappreciated roles of Fe–S clusters in CoV replication, and enable NiRAN-targeted antiviral development. Beyond SARS-CoV-2, these findings will inform strategies against emerging and future CoVs.


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: 2026 ( Subtotal = $771,179 )
2026	2026	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	6	7/16/2026	COMPETING CONTINUATION	$771,179
														Subtotal = $771,179

Issue Date FY: 2025 ( Subtotal = $620,543 )
2025	2025	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	002	5	8/12/2025	NON-COMPETING CONTINUATION	$620,543
2025	2023	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	001	3	1/8/2025	EXTENSION WITH OR WITHOUT FUNDS	$0
2025	2022	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	2	11/25/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $620,543

Issue Date FY: 2024 ( Subtotal = $620,543 )
2024	2024	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	001	4	9/4/2024	EXTENSION WITH OR WITHOUT FUNDS	$620,543
2024	2023	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	3	8/15/2024	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $620,543

Issue Date FY: 2023 ( Subtotal = $620,543 )
2023	2023	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	001	3	5/26/2023	EXTENSION WITH OR WITHOUT FUNDS	$620,543
2023	2022	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	2	5/26/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $620,543

Issue Date FY: 2022 ( Subtotal = $620,543 )
2022	2022	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	2	7/20/2022	NON-COMPETING CONTINUATION	$620,543
														Subtotal = $620,543

Issue Date FY: 2021 ( Subtotal = $638,072 )
2021	2021	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	1	8/6/2021	NEW	$638,072
														Subtotal = $638,072

Grand Total All Awards = $3,891,423

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Structure, function, and inhibition of the SARS-CoV-2 replication-transcription complex

Award Number: R01AI161278

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: 08/06/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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