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Deciphering the role of ddhCTP in viperin-related functions

Award Number: R01AI180133
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: 06/20/2024
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Deciphering the role of ddhCTP in viperin-related functions - Viperin (virus-inhibitory protein, endoplasmic reticulum-associated, interferon (IFN) inducible) is an interferon inducible protein that inhibits and/or is involved in the restriction of a remarkable range of both RNA and DNA viruses1-3. Viperin is a member of the radical S-adenosylmethionine (RS) superfamily of enzymes, all of which possess an oxygen-sensitive iron-sulfur cluster that is indispensable for catalytic activity. The mechanisms by which this 42 kDa enzyme elicits broad- spectrum antiviral activity remained a mystery until we recently discovered that viperin catalyzes the conversion of CTP to 3ʹ-deoxy-3′,4ʹ-didehydro-CTP (ddhCTP) through a radical-based mechanism. ddhCTP is a previously undescribed ribonucleotide, which acts as a chain terminator in vitro against several flavivirus RNA-dependent RNA polymerases (RDRP), including Dengue (DNV), West Nile (WNV), and Zika virus. Furthermore, we demonstrated that ddhCTP inhibited Zika virus replication in vivo. The discovery of ddhCTP provided, for the first time, a potential mechanism for some of viperin’s antiviral activities. However, one important caveat is that picornavirus RDRPs are not sensitive to ddhCTP, despite viperin serving as a restriction factor for these microbes. Viperin has also been implicated in several additional cellular processes important for viral replication and innate immunity, including cholesterol metabolism, fatty acid b- oxidation, protein turnover and ribosomal protein translation. These observations underly our major driving hypothesis that ddhCTP possesses additional critical roles in cellular metabolism that impact viral replication as well as other physiological processes. The objectives of this proposal are to provide biochemical, structural, and mechanistic insights into the roles that ddhCTP plays in the broader context of viperin-related functions.


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 = $734,139 )
2026	2026	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	3	4/17/2026	NON-COMPETING CONTINUATION	$734,139
														Subtotal = $734,139

Issue Date FY: 2025 ( Subtotal = $734,139 )
2025	2025	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	2	4/10/2025	NON-COMPETING CONTINUATION	$734,139
														Subtotal = $734,139

Issue Date FY: 2024 ( Subtotal = $781,139 )
2024	2024	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	001	1	7/11/2024	NEW	$0
2024	2024	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	1	6/20/2024	NEW	$704,726
2024	2024	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	002	1	9/4/2024	NEW	$76,413
														Subtotal = $781,139

Grand Total All Awards = $2,249,417

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Deciphering the role of ddhCTP in viperin-related functions

Award Number: R01AI180133

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: 06/20/2024

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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