# Project 2 - Novel Therapeutics for Emerging Alphavirus

> **NIH NIH U19** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2022 · $937,499

## Abstract

PROJECT SUMMARY
Mosquito-transmitted alphaviruses cause outbreaks of incapacitating acute and chronic arthritis and life-
threatening encephalitis. The arthritogenic alphaviruses include the re-emerging chikungunya (CHIKV),
Mayaro, and Ross River viruses. Since 2004, CHIKV has infected millions of people and expanded into
Europe, Asia, and Americas. As arthritis can endure for months to years after infection with an arthritogenic
alphavirus, large epidemics have severe economic consequences. The encephalitic alphaviruses include
Eastern, Venezuelan (VEEV), and Western equine encephalitis viruses that are endemic to the Americas and
infection can lead to mortality or long-term neurological sequelae. There are currently no approved alphavirus-
specific vaccines or antiviral agents. In collaboration with Southern Research, we used HTS to identify non-
toxic small molecules that inhibit CHIKV and VEEV replication. Additionally, we identified chemically distinct
compound classes that display broad inhibitory activity against alphaviruses, as well as other pathogenic
human viruses (e.g., flaviviruses). We also mapped resistance mutants against two highly active compounds
and identified the alphavirus nsP2 helicase domain and the nsP3 macrodomain as potential antiviral targets. In
addition to this work, in collaboration with the Emory Institute for Drug Development, we identified novel
nucleosides, which target RNA-dependent RNA polymerases, with potent antiviral activity against alphavirus
infection. Thus, we have identified potent antiviral compounds against three distinct molecular targets essential
for alphavirus replication. The goal of this highly interactive Project 2 of the Antiviral Drug Discovery and
Development Center (AD3C) is to develop new therapeutic strategies that inhibit alphavirus replication, prevent
selection for drug resistance, and reduce alphavirus disease severity. In Specific Aim 1, lead compounds will
be optimized in collaboration with Core A and Core B by iterative medicinal chemistry, cell culture-based
antiviral and cytotoxicity assays, and in vivo pharmacokinetic studies to improve their efficacy, selectivity,
solubility, and bioavailability. In Specific Aim 2, we will work with the other AD3C Projects to define the breadth
of antiviral activity and cell type specificity, molecular targets through resistance mapping and
structural/computational analyses and identify synergy profiles for compounds with potent activity. In Specific
Aim 3, optimized compounds will be evaluated for in vivo efficacy using well-established pre-clinical mouse
models of alphavirus infection. Since therapies that target different aspects of the viral life cycle are likely to
show improved efficacy and limit the development of drug resistance, combination therapies also will be tested.
Last of all, since alphavirus-induced disease includes inflammatory immune pathology, we will evaluate the
therapeutic potential of combining antiviral therapy with a...

## Key facts

- **NIH application ID:** 10380667
- **Project number:** 5U19AI142759-04
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** DANIEL N STREBLOW
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $937,499
- **Award type:** 5
- **Project period:** 2019-03-07 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10380667

## Citation

> US National Institutes of Health, RePORTER application 10380667, Project 2 - Novel Therapeutics for Emerging Alphavirus (5U19AI142759-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10380667. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*