# Project 3 – Direct-Acting Antivirals against Paramyxoviruses

> **NIH NIH U19** · EMORY UNIVERSITY · 2022 · $5,393,007

## Abstract

The paramyxovirus (PMV) family contains some of the most contagious viruses known to infect humans such as
measles (MeV) and mumps (MuV) virus, and some of the deadliest like Hendra (HeV) and Nipah (NiV) virus.
The latter is listed on the WHO R&D blueprint as a pathogen of pandemic concern and has caused repeated
deadly outbreaks when spilled over from bats into the human and animal populations. Bats are hosts to major
mammalian paramyxoviruses, including the henipaviruses and other emerging pandemic threats. In support of
our center’s (AC/DC) primary mission to develop orally available direct-acting clinical candidates against existing
and emerging pandemic viral threats, Project 3 (P3) will test, characterize, and optimize the leading antiviral hits
AC/DC has already discovered against paramyxoviruses of potential pandemic concern (P3CO). Our focus is
on developing orally efficacious nucleoside analog and non-nucleoside RNA polymerase inhibitors. These target
the conserved viral RNA-dependent RNA polymerase (RdRP) in mechanistically distinct ways and will ensure a
pipeline of structurally diverse chemotypes active against P3CO. EIDD-2749 and GHP-88309 are exemplar
NRPI and NNRPI chemotypes that are orally bioavailable, active against multiple genera of PMVs, have a wide
safety margin (SI>500), favorable PK that allow for once or twice daily dosing, and have non-overlapping and
fitness limiting resistance profiles. EIDD-2749 also has proven efficacy against SARS-CoV-2 (P1) and the viruses
targeted by P5 and P6. These two compounds exemplify the hits that will drive the re-iterative chemotype-to-
phenotype optimization and advanced characterization processes that underly the primary goal of P3, which is
to develop orally bioavailable, structurally diverse, broad spectrum anti-PMV therapeutics with clinically and
pharmacologically attractive properties that warrant formal IND development. Our driving hypothesis is that
conserved structural and functional features of the PMV RdRP will allow for development of orally efficacious
direct-acting antivirals. We will leverage the collective expertise and integrated resources of AC/DC (Cores A-
F) to achieve our goal and test our hypothesis via the following four specific aims: we will characterize the efficacy
parameters of nucleoside analogs as clinically relevant inhibitors of henipavirus replication (aim 1); we will
develop non-nucleoside RNA polymerase inhibitors that target henipavirus replication complexes to complement
or enhance nucleoside analog RNA polymerase inhibitor therapy (aim 2); we will evaluate the potential of both
nucleoside analog and non-nucleoside RNA polymerase inhibitors as therapeutic drug candidates for
morbilliviruses (aim 3); and we will discover new chemotypes that inhibit divergent paramyxovirus replication
(aim 4).

## Key facts

- **NIH application ID:** 10513944
- **Project number:** 1U19AI171403-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Benhur Lee
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $5,393,007
- **Award type:** 1
- **Project period:** 2022-05-16 → 2026-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10513944

## Citation

> US National Institutes of Health, RePORTER application 10513944, Project 3 – Direct-Acting Antivirals against Paramyxoviruses (1U19AI171403-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10513944. Licensed CC0.

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