# Project 4 - Inhibitors of Flavivirus Replication

> **NIH NIH U19** · EMORY UNIVERSITY · 2022 · $2,911,345

## Abstract

Emerging and endemic members of the genus Flavivirus pose significant worldwide public health threats. The
global ranges of dengue viruses, Japanese encephalitis virus, West Nile virus (WNV), tick-borne encephalitis
virus and ZIKV have recently expanded. Dengue virus is estimated to infect ~400 million, cause illness in ~100
million, and kill ~21,000 people a year. Yellow fever virus remains a public health concern in 34 African countries
and 13 South American countries. Newly emerging flaviviruses include Powassan virus (POWV) (northeast US
and Canada) and Usutu virus (Europe). Vaccines are available for humans for only some flaviviruses, but they
are not always used. A few individuals develop multiorgan disease after vaccination with the live 17D yellow
fever vaccine which is typically fatal. There are currently no effective flavivirus-specific small molecule
therapeutics for treatment of humans with flavivirus infections. The goal of the research proposed in Project 4 of
the AC/DC is to develop clinical candidate compounds that can be delivered orally, have broad anti-flavivirus
activity and directly act on a viral component. Under Aim 1, we will develop four ribonucleoside analogs
synthesized by Core
B, for which preliminary data indicating anti-flavivirus activity has already been obtained, by
a reiterative analog synthesis-biological testing strategy with Cores B and C. Compounds will be tested for
antiviral activity against a panel of flaviviruses and cytotoxicity in primary mouse and human macrophages and
neural cells. Mode of action and development of drug resistance will also be analyzed. Under Aim 2, reporter
POWV and WNV viruses will be generated and used in high throughput screening of ~300,000 unique
compounds under BSL3 containment by Core F. Hits validated by counter-screening will be further developed
under Aim 1. Compounds meeting the advancement criteria will be tested for in vivo efficacy in flavivirus mouse
and hamster infection models and in human cortical organoids. The effect of the gut microbiome on the activity
of lead flavivirus antiviral compounds will be assessed in collaboration with Project 7. The impact of antiviral
treatment on acute and chronic virus-induced neurological signatures in POWV and WNV infected animals and
organoids will be evaluated in collaboration with Project 2. Core D will provide whole genome sequencing of viral
mutants generated during viral resistance profiling of lead compounds.

## Key facts

- **NIH application ID:** 10513945
- **Project number:** 1U19AI171403-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Margo A Brinton
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,911,345
- **Award type:** 1
- **Project period:** 2022-05-16 → 2026-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10513945

## Citation

> US National Institutes of Health, RePORTER application 10513945, Project 4 - Inhibitors of Flavivirus Replication (1U19AI171403-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10513945. Licensed CC0.

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