# Development of Antivirals against Filovirus Replication

> **NIH NIH U19** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $3,796,046

## Abstract

SUMMARY (Project 3: Kawaoka)
As part of the Rapidly Emerging Antiviral Drug Development Initiative-AViDD Center (READDI-AC) program, the
goal of Project 3: Filoviruses is to identify and develop promising hit and lead compounds with robust anti-
filovirus activity, while also advancing the field of filovirus drug development through the identification of new
chemical entities and druggable targets. In Aim 1 (‘Identification of compound hits and conserved filovirus
druggable target sites’), a multipronged approach will be used to identify hit compounds by using different
screening assays including targeted nucleoside libraries, a DNA-encoded library screen, enzyme-based
screens, and promising compounds from other Projects. We will also identify and validate druggable target sites
in the functional domains of the filovirus polymerase (L) protein by using AlphaFold and fragment mapping, which
may be applicable to the discovery of additional broadly active anti-filovirus small molecule compounds by
Discovery Core B. After hit compounds are prioritized by Adman Core A and MedChem Core D, in Aim 2
(‘Optimization of hit compounds against filoviruses’) 2–4 hit series will be identified for Hit-to-Probe optimization
by MedChem Core D. This core will synthesize compound analogs for antiviral evaluation, improve upon their
activity via structural-activity relationship studies, and determine their drug absorption, distribution, metabolism,
excretion and pharmacokinetic (PK) properties. In addition to hit compounds identified in Aim 1, we will bring
into this program, two hit nucleoside analogs against filoviruses through a collaboration with Dr. Seley-Radtke,
a co-investigator. The antiviral activity of the compounds and synthesized analogs will be evaluated for antiviral
breadth in enzyme-based assays by Enzymology Core C and in cell-based assays using a novel Ebola reporter-
virus system and authentic filoviruses by Project 3. Two lead compounds will advance into Aim 3 (‘Lead
development to establish in vivo efficacy’), where the studies will be carried out to generate a pre-clinical
package. With input from MedChem Core D, formulation and in vivo PK studies to gain a better understanding
of the PK properties of the compounds for their advancement to in vivo antiviral efficacy studies will be carried
out by contracted research organizations. Antiviral efficacy studies will be carried out by Project 3, first in rodent
models of filovirus infection, followed by confirmatory studies in a ferret model. Ultimately, we expect to deliver
targets, hits, leads, and chemical probes for public crowd-sharing, and pre-IND enabling data for one compound
with antiviral activity against at least three important Ebola viruses, and possibly Marburg virus, to the stage of
early in vivo optimization with the goal of attracting an industry partner(s) to eventually move the drug to clinical
trials.

## Key facts

- **NIH application ID:** 10513686
- **Project number:** 1U19AI171292-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Ralph S Baric
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $3,796,046
- **Award type:** 1
- **Project period:** 2022-05-16 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10513686

## Citation

> US National Institutes of Health, RePORTER application 10513686, Development of Antivirals against Filovirus Replication (1U19AI171292-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10513686. Licensed CC0.

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