# Development of direct-acting flavivirus inhibitors

> **NIH NIH U19** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $3,957,517

## Abstract

ABSTRACT
Development of potent and broad-spectrum direct acting antivirals (DAAs) is key as a first-line defense
against diseases caused by flaviviruses (e.g., dengue virus, yellow fever virus, West Nile virus, Japanese
encephalitis virus, Zika virus and tick-borne encephalitis virus). To promote global health, the underlying
premise of this proposal is to combine expertise and cutting-edge technology of academic and
pharmaceutical sectors to establish a robust environment for drug identification and commercialization. The
envisioned development process of broad-spectrum DAAs against flaviviruses is divided in three stages (aim
1–3). The first aim entails the identification and validation of conserved flavivirus targets and hits
(driven by Discovery Core B and the Enzymology Core C. Already identified RNA-dependent RNA
polymerase (RdRp) hits will serve as the chemical starting point for further optimization by MedChem Core
D. In addition, in collaboration with the Discovery Core B, we aim to identify novel structurally conserved
binding pockets of the following key viral replication enzymes: nonstructural protein 5 (NS5) RdRp, NS3
helicase, and NS2B-NS3 protease. Compounds targeting those sites will be explored using virtual docking,
targeted small-molecule and fragment-based high- throughput screens and DNA-encoded chemical library
(DEL) screens. Target sites will be validated in enzymatic assays. We will determine the role of key amino
acids in enzyme activity, viral replication and fitness through protein engineering. At least two to four hit
series will then be optimized and tested in aim 2 (Hit to Lead). Compounds will be characterized for
activity in biochemical and cell-based viral replication assays, for favorable in vitro drug absorption,
distribution, metabolism, excretion and toxicity (ADME-TOX), mechanism of action and resistance. Our
heterogeneous flavivirus panel will assess the level of broad-spectrum antiviral activity in diverse cell types.
While we aim to develop broad-spectrum anti-flavivirus drugs, several flaviviruses cause significant human
disease globally, so highly selective inhibitors will also be pursued as appropriate. Lead compounds will be
shared with Projects 1, 2, 3, and 5 to evaluate breadth across other viral families. At least two lead
compounds selected in aim 2 will be tested in aim 3 for in vivo efficacy. After proof of concept in an in
vivo study, we anticipate to deliver one Flavivirus inhibitor active against at least one flavivirus, or at best
against all flaviviruses described in this proposal, ready to start Investigational New Drug Application (IND)/
Clinical Trial Authorization (CTA)-enabling studies, and subsequently if approved, enter clinical development
and start Phase1 studies.

## Key facts

- **NIH application ID:** 10513687
- **Project number:** 1U19AI171292-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Ralph S Baric
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $3,957,517
- **Award type:** 1
- **Project period:** 2022-05-16 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10513687

## Citation

> US National Institutes of Health, RePORTER application 10513687, Development of direct-acting flavivirus inhibitors (1U19AI171292-01). Retrieved via AI Analytics 2026-06-03 from https://api.ai-analytics.org/grant/nih/10513687. Licensed CC0.

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