# Development of Broad Spectrum Direct Acting Antivirals Against Emerging Alphaviruses

> **NIH NIH U19** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $7,100,428

## Abstract

ABSTRACT
Alphaviruses (Togaviridae genus) several medically important viruses, including chikungunya virus (CHIKV),
Venezuelan equine encephalitis virus (VEEV), and Eastern equine encephalitis virus (EEEV). These re-
emerging viruses are categorized as Biodefense Category B and C priority pathogens due to their pandemic
risk or potential as bioterror threats. Despite the threat posed by these viruses, there are no approved antivirals
for treating any alphavirus infection. Therefore, our highly experienced and interactive team will leverage our
world class expertise in alphavirus biology, structural biology, high throughput screening, medicinal chemistry,
and drug development to generate small molecule inhibitors targeting conserved viral enzymes with the goal of
producing new, broad spectrum, direct acting anti-alphaviral drugs. The central premise of this effort is that
small molecule-based inhibitors of essential viral proteins across multiple members of the Alphavirus family can
be developed employing a platform that (a) integrates target identification and validation (Aim 1), (b) confirms
and optimizes cellular antiviral activity and SAR against the given target (Aim 2a), (c) establishes and improves
in vitro ADME and in vivo pharmacokinetics (Aim 2b), and progresses leads into in vivo efficacy and toxicity
animal models (Aim 3). Collaboration with the Discovery Core B will functionally validate structurally conserved
compound binding pockets in alphaviruses enzymes (RNA dependent RNA polymerase (RDRP; nsP4), the RNA
helicase (nsP2), and the nsP2 protease). These analyses will inform the selection of viral targets for hit discovery
using a combination of physical and in silico screening in coordination with Core B. Hit compounds that show
robust target engagement will be optimized in collaboration with the Medicinal Chemistry Core (Core C) for target
inhibition, stability, selectivity, solubility, permeability, pharmacokinetics, and antiviral activity in vitro against
multiple alphaviruses (CHIKV, EEEV, and VEEV). As our goal is to identify broadly active compounds, lead
compounds will also be tested agAainst additional alphaviruses (e.g. RRV, MAYV, ONNV, WEEV, and SINV)
and other viruses in our program, including coronaviruses (Proj. 1 and 2), flaviviruses (Proj. 4), and filoviruses
(Proj. 5). We will also collaborate with Enzymology Core D to identify their antiviral mechanism of action. Lead
compounds with optimal in vivo biodistribution and stability will be tested for in vivo antiviral efficacy using our
established models of alphavirus-induced arthritis (CHIKV) or encephalitis (VEEV or EEEV). Candidates with
potent in vivo antiviral efficacy will be further optimized for formulation, toxicity, and advanced PK/PD.

## Key facts

- **NIH application ID:** 10513688
- **Project number:** 1U19AI171292-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Mark T Heise
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $7,100,428
- **Award type:** 1
- **Project period:** 2022-05-16 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10513688

## Citation

> US National Institutes of Health, RePORTER application 10513688, Development of Broad Spectrum Direct Acting Antivirals Against Emerging Alphaviruses (1U19AI171292-01). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10513688. Licensed CC0.

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