# Development of Benzodiazepine YFV NS4B inhibitors as therapeutic agents for Yellow Fever

> **NIH NIH R01** · BARUCH S. BLUMBERG INSTITUTE · 2021 · $692,067

## Abstract

ABSTRACT
This is a proposal to develop a highly selective and potent antiviral benzodiazepine compound against yellow
fever virus (YFV) as a therapeutic agent for treatment of yellow fever and understand its antiviral mechanism.
Yellow fever is an acute viral hemorrhagic disease which threatens approximately one billion people living in
tropical areas of Africa, Central and South America. Although a highly effective yellow fever vaccine has been
available for more than seven decades, the low vaccination rate fails to prevent outbreaks in at-risk regions. It
has been estimated that up to 1.7 million YFV infections occur in Africa each year, resulting in 29,000 to
60,000 deaths, which outnumber the estimated death toll of global dengue virus infection. Thus far, there is no
specific antiviral treatment for yellow fever. To cope with this medical challenge, we discovered an acetic acid
benzodiazepine (BDAA) compound that potently inhibited YFV replication in both mammalian and insect cells
by targeting the viral non-structural 4B (NS4B) protein. We have already demonstrated in YFV-infected
hamsters that oral administration of BDAA significantly protected the animals from death, reduced viral load by
greater than 2 logs and attenuated viral infection-induced liver injury and body weight loss. Building on these
encouraging preclinical studies, we propose in this project to optimize the lead compound to obtain
benzodiazepine derivatives with improved solubility and reduced plasma protein binding ability to achieve
improved in vivo antiviral efficacy and safety profile. Meanwhile, we will continue our efforts toward
understanding the molecular mechanism by which BDAA and its derivatives inhibit YFV replication.
Specifically, impacts of the compound on NS4B protein metabolism, integrity and function of viral RNA
replication complex as well as YFV interaction with host cellular innate immune response will be investigated.
At the completion of this project, we will nominate an optimized benzodiazepine derivative as well as backup
compounds for further preclinical/clinical development. In addition to knowing how the compound inhibits YFV
replication, our studies proposed in this project should also enrich our knowledge on the function of NS4B
protein in YFV replication and evasion of host innate immunity.

## Key facts

- **NIH application ID:** 10134226
- **Project number:** 5R01AI134732-04
- **Recipient organization:** BARUCH S. BLUMBERG INSTITUTE
- **Principal Investigator:** Jinhong Chang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $692,067
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134226

## Citation

> US National Institutes of Health, RePORTER application 10134226, Development of Benzodiazepine YFV NS4B inhibitors as therapeutic agents for Yellow Fever (5R01AI134732-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10134226. Licensed CC0.

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