# Development and validation of antivirals against Flaviviruses

> **NIH NIH U19** · SCRIPPS RESEARCH INSTITUTE, THE · 2022 · $1,634,345

## Abstract

SUMMARY
Flaviviruses cause hundreds of millions of infections annually and a range of clinical syndromes including
hemorrhagic fever, encephalitis, liver failure, and congenital disease. Currently, and despite extensive screening
campaigns by academic and pharmaceutical laboratories, there are no specific therapeutics against these
viruses and a paucity of available vaccines. Our goal is to use innovative screening assays and novel viral protein
targets to develop combinations of orally-formulated direct acting antivirals that can treat existing and emerging
flaviviruses. We will develop antivirals against three essential proteins in flaviviruses. First, given that nucleoside
analogs are an important class of antivirals we will develop orally bioavailable pan-antiflaviviral nucleoside
analogs. We have in hand two scaffolds we are developing and will screen libraries of nucleosides for new
scaffolds. As nucleosides can be broadly active, we will test the most active nucleosides against additional RNA
viruses focusing on emerging viruses (e.g., SARS-CoV-2, EBOV, LASV and SFTSV) that are in our CAMPP
consortium. Since flaviviruses are small RNA viruses and encode few proteins, we will develop antivirals against
two of these essential protens with no known enzymatic activity: NS4A and NS1. Recently, clinically approved
antiviral against the distantly related hepatitis C virus NS5B blocks infection of this non-enzymatic target. We
have identified an inhibitor of ZIKV NS4A, an essential non-enzymatic viral protein, as a possible antiviral drug.
As part of our program, we will use medicinal chemistry and SAR to optimize and broaden its activity against
additional flaviviruses. NS1 serves a scaffold for replication complexes in the cytoplasm at the endoplasmic
reticulum and also functions extracellularly to promote vascular leakage and central nervous system invasion by
binding to endothelial cells and antagonizing innate immunity. We will use biochemical assays to identify drugs
that bind flavivirus NS1 and then screen them for blockade of its intracellular and/or extracellular functions. Drugs
that can block the functional activity of NS1 may impact viral replication and steps in pathogenesis. For those
inhibitors against NS5, NS4A or NS1 that show optimal bioavailability and efficacy profiles, with in vivo levels
that at several fold above their cellular EC90 values, we will advance into animal models of flavivirus infection. In
addition, we will determine the barrier to resistance, test combinations of inhibitors first in vitro and ultimately in
vivo to increase potency and prevent the emergence of resistance.

## Key facts

- **NIH application ID:** 10514328
- **Project number:** 1U19AI171443-01
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Sara Cherry
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,634,345
- **Award type:** 1
- **Project period:** 2022-05-16 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10514328

## Citation

> US National Institutes of Health, RePORTER application 10514328, Development and validation of antivirals against Flaviviruses (1U19AI171443-01). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10514328. Licensed CC0.

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