# Development of Inhibitors Targeting Flavivirus Methyltransferase

> **NIH AI R01** · UNIVERSITY OF ARIZONA · 2026 · $767,382

## Abstract

Abstract:
Flaviviruses are primarily insect-borne, associated with global morbidity and mortality, and found on every
inhabited continent. Unfortunately, current therapeutic options for treating diseases associated with these viruses
are limited. All flaviviruses encode methyltransferases (MTases)—flaviviral NS5 for both N-7 and 2'-O
methylations of viral genomic RNA. The N-7 MTase function is essential for replication of the viral RNA genome,
whereas 2'-O MTase function is required for the virus to evade the host innate immune response. These activities
are conserved among the flaviviruses. For this project, our collaborative team will optimize the current lead
compounds, perform high throughput screening (HTS) to identify additional lead candidates, chemically optimize
the lead candidates, and define structure activity relationships. Optimizing current lead compounds using cutting-
edge medicinal chemistry, the team will perform a large scale HTS campaign using innovative fluorescence
chemical probes to identify additional small molecule inhibitors of flavivirus RNA capping MTases. We will
perform an in-depth investigation of the model of action and antiviral efficacy using in vitro biochemistry, structural
biology, virology, in vivo pharmacokinetics, and in vivo animal models, which will allow the development of novel,
effective, broad-spectrum, and druglike therapeutic agents against both flaviviruses. Preliminary progress has
been made in the identification of initial lead inhibitors of these MTases, demonstrating low nanomolar antiviral
activity. We will advance these compounds to further develop potent antiviral compounds while conducting large-
scale screening in parallel for additional structural scaffold discoveries. Complementary expertise among our
investigators will synergize and expedite the progress of this research. Our collaborative objective is to provide
first-in-class drug candidates for the treatment or prevention of these viral infections.

## Key facts

- **NIH application ID:** 11374858
- **Project number:** 5R01AI175435-04
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** HONGMIN  LI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** AI
- **Fiscal year:** 2026
- **Award amount:** $767,382
- **Award type:** 5
- **Project period:** 2023-04-07T00:00:00 → 2028-03-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11374858

## Citation

> US National Institutes of Health, RePORTER application 11374858, Development of Inhibitors Targeting Flavivirus Methyltransferase (5R01AI175435-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11374858. Licensed CC0.

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