# Validating the Flavivirus Envelope Protein as an Antiviral Target

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $961,202

## Abstract

PROJECT SUMMARY
 Dengue virus (DENV) and other flaviviruses are major human pathogens that cause significant disease.
Transmitted by widespread mosquito species, many of these viruses spread rapidly and can have a
devastating impact on public health where prior immunity does not exist. There is thus a significant need for
countermeasures to combat both current and future flavivirus threats. Major limitations in current antivirals
development are the relatively small number of validated antiviral targets, most of which are viral enzymes
(e.g., polymerases, proteases); the low barrier to resistance when direct-acting antivirals are used as
monotherapies; and the narrow spectrum activity of most of these agents (“one bug, one drug”). New classes
of targets that can mediate broad-spectrum activity against related viruses and that have high barriers to
resistance are particularly needed to combat emerging viruses since we generally lack sufficient time and
resources to develop new drugs on a useful time scale once these viruses pose significant threats.
 Small molecules targeting the flavivirus envelope protein, E, have the potential to mimic the humoral
immune response by engaging their target extracellularly and blocking viral entry early in the replication cycle.
We have identified multiple small molecule inhibitor series that bind to the DENV envelope protein, E, and
inhibit E-mediated membrane fusion during viral entry even when only a minority of copies of E on the particle
are inhibitor-bound. These compounds bind in a pocket between domains I and II and inhibit West Nile, Zika,
and Japanese encephalitis viruses due to at least partial conservation of this site. We recently established a
target-based assay and validated its use in the identification of new inhibitors of DENV and Zika E proteins
that bind in the conserved pocket and that have more drug-like properties than our original inhibitors. Building
on this work, we now propose a comprehensive plan to rationally optimize small molecule inhibitors of the
DENV E protein as a potential anti-viral strategy. Towards this end, we will combine modeling and structure-
guided drug design with an efficient screening cascade using complementary target-based biochemical,
cellular and mechanistic assays to enable efficient optimization of two chemically distinct lead series. Our
primary goal in this work is to demonstrate antiviral efficacy in a murine model of DENV infection, thus laying
the foundation for first-in-class direct acting antivirals to treat the growing global threat that DENV poses.

## Key facts

- **NIH application ID:** 10798141
- **Project number:** 5R01AI146152-06
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** NATHANAEL Schiander GRAY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $961,202
- **Award type:** 5
- **Project period:** 2020-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10798141

## Citation

> US National Institutes of Health, RePORTER application 10798141, Validating the Flavivirus Envelope Protein as an Antiviral Target (5R01AI146152-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10798141. Licensed CC0.

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