# Deciphering the role of ddhCTP in viperin-related functions

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2024 · $781,139

## Abstract

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.

## Key facts

- **NIH application ID:** 10780944
- **Project number:** 1R01AI180133-01
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Tyler L Grove
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $781,139
- **Award type:** 1
- **Project period:** 2024-06-20 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10780944

## Citation

> US National Institutes of Health, RePORTER application 10780944, Deciphering the role of ddhCTP in viperin-related functions (1R01AI180133-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10780944. Licensed CC0.

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